aryl aryl bond formation by transition-metal-catalyzed ...aether.cmi.ua.ac.be/artikels/artikels...

Aryl −Aryl Bond Formation by Transition-Metal-Catalyzed Direct Arylation

Dino Alberico, Mark E. Scott, and Mark Lautens*

Davenport Laboratories, Chemistry Department, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6

Received July 6, 2006

Contents1. Introduction 1742. Direct Arylation of Aryl C−H Bonds 175

2.1. Intermolecular Aryl−Aryl Bond Formation 1772.1.1. Direct Arylation via Transition-Metal

Cascade Reactions Involving Alkenes andAlkynes

177

2.1.2. Directing Group-Assisted Arylation ofFunctionalized Aromatic Hydrocarbons

181

2.1.3. Direct Arylation of Aromatic Hydrocarbonsin the Absence of a Directing Group

191

2.2. Intramolecular Aryl−Aryl Bond Formation 1922.2.1. Scope and Limitations 1922.2.2. Applications 203

3. Direct Arylation of Heteroaryl C−H Bonds 2113.1. Direct Arylation of Nitrogen-Containing

Heteroaryl Compounds211

3.1.1. Indoles and Azaindoles 2113.1.2. Pyrroles 2183.1.3. Pyridines and Quinolines 2203.1.4. Other Nitrogen-Containing

Heteroaromatics221

3.2. Direct Arylation of Furans and Thiophenes 2283.2.1. Intramolecular Aryl−Furyl and

Aryl−Thiophenyl Bond Formation228

3.2.2. Intermolecular Aryl−Furyl andAryl−Thiophenyl Bond Formation

229

4. Conclusions 2335. Notations and Abbreviations 2336. Acknowledgments 2347. References 234

1. IntroductionThe biaryl structural motif is a predominant feature in

many pharmaceutically relevant and biologically activecompounds. As a result, for over a century1 organic chemistshave sought to develop new and more efficient aryl-arylbond-forming methods. Although there exist a variety ofroutes for the construction of aryl-aryl bonds, arguably themost common method is through the use of transition-metal-mediated reactions.2-4 While earlier reports focused on theuse of stoichiometric quantities of a transition metal to carryout the desired transformation, modern methods of transition-metal-catalyzed aryl-aryl coupling have focused on thedevelopment of high-yielding reactions achieved with excel-lent selectivity and high functional group tolerance under

mild reaction conditions. Typically, these reactions involveeither the coupling of an aryl halide or pseudohalide withan organometallic reagent (Scheme 1), or the homocouplingof two aryl halides or two organometallic reagents. Althougha number of improvements have developed the formerprocess into an industrially very useful and attractive methodfor the construction of aryl-aryl bonds, the need still existsfor more efficient routes whereby the same outcome isaccomplished, but with reduced waste and in fewer steps.In particular, the obligation to use coupling partners that areboth activated is wasteful since it necessitates the installationand then subsequent disposal of stoichiometric activatingagents. Furthermore, preparation of preactivated aryl sub-strates often requires several steps, which in itself can be atime-consuming and economically inefficient process.

An attractive alternative to this approach is to treat thearyl C-H bond as a functional group, in analogy to acarbon-metal or carbon-halogen bond. The simplest ap-proach would involve the coupling of two aryl C-H bondsto give the corresponding biaryl product (Scheme 2),although this process is unfavorable from a thermodynamicperspective due to the high bond strength of an aryl C-Hbond (e.g., the homocoupling of benzene to give biphenyland hydrogen is thermodynamically disfavored by 13.8kJ/mol).5 Furthermore, while such an approach is alluring,the ubiquitous and diverse nature of C-H bonds in complexorganic compounds makes a regioselective oxidative cou-pling of this type a formidable challenge.

One solution which addresses the thermodynamic issueas well as the need for stoichiometric activating agents onboth coupling partners is to use a preactivated aryl substrateas one coupling partner and a simple unactivated arylsubstrate as the other (Scheme 3). Although the advantagesof this strategy for aryl-aryl coupling have made it a populartopic of research since the first reports over 20 years ago,the more subtle issue of C-H bond regioselectivity remainsunsolved in some systems.

While the coupling of an aryl halide or pseudohalide withan organometallic reagent is commonly referred to as a cross-coupling reaction, several terms such as C-H (bond)activation, C-H (bond) functionalization, cross-dehaloge-native coupling, and catalytic direct arylation have been usedto describe the corresponding coupling of an aryl halide orpseudohalide with a simple arene (Scheme 3).6-8 Althoughthe former two terms are more prevalent in the literature,we have elected to use the term direct arylation, which wedefine as the direct coupling of a nonactivated aryl C-Hbond with an activated arene. This term best describes theoverall process illustrated in Scheme 3, while additionallypreventing any erroneous implications regarding the mecha-nistic pathway by which the process occurs.

* To whom correspondence should be addressed. E-mail: [email protected].

174 Chem. Rev. 2007, 107, 174−238

10.1021/cr0509760 CCC: $65.00 © 2007 American Chemical SocietyPublished on Web 01/10/2007

Despite the fact that several reviews on this topic haveappeared as sections of other reviews3,8-18 and books,19-22

in most cases only a general overview was given, or thereview was limited in that it emphasized the author’s ownwork. In this review we will outline the development andadvances in transition-metal-catalyzed aryl-aryl bond for-mation by direct arylation, as well as its application to thesynthesis of important compounds including natural products,pharmaceuticals, catalyst ligands, and materials. Additionally,this review is organized into the direct arylation of aryl andheteroaryl C-H bonds (Scheme 4), and does not includeexamples using stoichiometric amounts of transition metals.Furthermore, this review will not discuss aryl-aryl bondformation via oxidative coupling reactions of the typeoutlined in Scheme 2. Instead, the reader is directedelsewhere23,24 for references on this topic.

2. Direct Arylation of Aryl C −H BondsReaction Conditions. Although a variety of transition

metals have been used for the formation of aryl-aryl bonds,second-row transition metals in low oxidation states (Rh, Ru,Pd) have emerged as the preferred catalysts in catalytic direct

Dino Alberico was born in Hamilton, Ontario, Canada, in 1976. He receivedhis B.Sc. degree from McMaster University in 1999. In 2001 he receivedhis M.Sc. degree from the University of Guelph under the supervision ofAdrian L. Schwan, where he studied Diels−Alder reactions of R,â-unsaturated sulfinate esters. He then joined the research group of MarkLautens at the University of Toronto and received his Ph.D. degree in2005. His research focused on norbornene-mediated palladium-catalyzedannulation reactions. He is currently pursuing postdoctoral work at theUniversite de Montreal with Andre B. Charette.

Mark E. Scott was born in Simcoe, Ontario, Canada, in 1977. He receivedhis bachelor degree (honors) in engineering chemistry at Queen’sUniversity in 2000. In 2002, he received his M.Sc.Eng. in chemicalengineering from Queen’s University under the supervision of Profs. ScottParent and Ralph Whitney. He is currently a Ph.D. candidate in MarkLautens’ research group at the University of Toronto, where he is studyingthe Lewis acid-mediated ring expansion of methylenecyclopropanes. Hehas been the recipient of an NSERC Postgraduate (M.Sc.Eng.) Scholarshipand an NSERC Postgraduate (Ph.D.) Scholarship. He will be pursuinghis postdoctoral studies at Harvard University under the supervision ofProf. David A. Evans following the completion of his Ph.D.

Scheme 1

Scheme 2

Mark Lautens was born in Hamilton, Ontario, Canada, on July 9, 1959.He obtained his undergraduate degree in chemistry at the University ofGuelph, where he graduated with distinction in 1981. He attended theUniversity of WisconsinsMadison, where he was awarded a Ph.D. in1985 under the supervision of Barry M. Trost while supported by anNSERC Postgraduate Scholarship. From 1985 to 1987 he was an NSERCPostdoctoral Fellow working in the laboratories of David A. Evans atHarvard University. In 1987 he was appointed as an Assistant Professorand University Research Fellow at the University of Toronto. In 1992 hewas promoted to Associate Professor, and in 1995 he became Professorof Chemistry. Since 1998 he has held the AstraZeneca Chair in OrganicSynthesis, and in 2003 he became an Industrial Research Chair supportedby Merck Frosst and NSERC. He has received a number of awardsincluding an Eli Lilly Granteeship, an A.P. Sloan Fellowship, and an E.W.R.Steacie Fellowship. He was awarded the Rutherford Medal in Chemistryfrom the Royal Society of Canada, the Alfred Bader Award, and the R.W.Lemieux Award from the Canadian Society for Chemistry. In 2001 hewas elected as a Fellow of the Royal Society of Canada, and in 2006 hewas selected as an A.C. Cope Scholar from the American ChemicalSociety. Throughout his career he has been interested in metal-catalyzedtransformations that make carbon−carbon and carbon−heteroatom bondsas well as asymmetric catalysis. His work has appeared in nearly 200publications, reviews, and book chapters. He edited Volume 1 of Scienceof Synthesis and is an Editor of Synthesis and Synfacts.

Scheme 3

Aryl−Aryl Bond Formation by Direct Arylation Chemical Reviews, 2007, Vol. 107, No. 1 175

arylation reactions. In some cases, the high reactivity of thetransition-metal complexes employed in direct arylationreactions has allowed for the use of extremely low catalystloadings (as low as 0.1 mol %), making them industriallyattractive.

The ligands used in direct arylation depend on the natureof the aryl halide being used. For more reactive aryl iodides,moderately electron-rich monodentate phosphines such asPPh3 are typically used. These same phosphines have alsobeen successfully utilized for aryl bromides, although in somesystems far superior yields have been obtained using pal-ladium and more sterically bulky and electron-rich trialkyl-phosphine or Buchwald’s biphenylphosphines.25 Recently,the use of aryl chlorides in a palladium-catalyzed directarylation reaction has also been reported. However, as inother cross-coupling reactions,26 the low reactivity of theC-Cl bond to oxidative addition necessitated the use ofelectron-rich and sterically-hindered trialkylphosphines, Buch-wald’s biphenylphosphines, orN-heterocyclic carbene ligandsto achieve synthetically useful yields of the direct arylationproduct. It should also be noted that ligand-free conditions(Jeffery’s conditions) have also been successfully used inpalladium-catalyzed direct arylation reactions for a varietyof aryl halides.

While base is generally required in direct arylationreactions,27 in most cases the exact role of the base remainsunclear. Some recent evidence, however, suggests that insome systems the base may be intimately involved in theformation of the diarylpalladium(II) species (and not simplyas a bystander whose role is to regenerate the activecatalyst).7,28,29 Typically, inorganic bases such as K2CO3,Cs2CO3, KOAc, t-BuOK, and CsOPiv are used. In particular,cesium carbonate and CsOPiv have proven to be veryeffective in many cases due to increased solubility in organicsolvents. While polar, aprotic solvents such as DMF, DMA,CH3CN, NMP, and DMSO are commonly used, nonpolarsolvents such as toluene and xylene have also been employedsuccessfully. In addition, temperatures>100°C are typicallyused, and in most cases heating for several hours to days isnecessary.

Regioselectivity.Direct arylation reactions can take placein either an intermolecular or an intramolecular fashion(Scheme 5). While intramolecular direct arylation reactions

employ tethers to limit the degree of freedom in a system,thereby controlling the regioselectivity of the reaction (eq1, Scheme 5), intermolecular direct arylation reactions presenta more formidable task since the catalyst has a greater degreeof freedom when reacting at the C-H bond. Two factorsthat influence the regioselectivity of the intermolecular directarylation are the electronics of the arene being functionalized(eq 2, e.g., the reaction occursortho or para to the electron-donating group via an electrophilic aromatic substitutionprocess), and more commonly the directing group. Typically,directing group-assisted reactions employ nitrogen- andoxygen-coordinating functional groups to direct the arylation(eq 3), although in some cases external alkenes or alkynesin a cascade process have been used to create a “directing”alkyl- or alkenylmetal species in situ (eq 4).

This concept of using a directing group to control theregioselectivity of the subsequent transition-metal insertioninto a C-H bond was first reported by Kleinman and Dubeckover 40 years ago (Scheme 6).30

Since this initial report, the preparation and use ofmetallacycles not only as mechanistic tools but also as highlyactive precatalysts has been extensively reported.31-33 Gener-

Scheme 4

Scheme 5

Scheme 6

176 Chemical Reviews, 2007, Vol. 107, No. 1 Alberico et al.

ally, these metallacycles are obtained through the use of acoordinating group that aids in directing the subsequenttransition-metal C-H bond insertion, usually resulting in theformation of either the kinetically or thermodynamicallyfavored five- or six-membered metallacycle. It is this sameapproach that is often employed in direct arylation chemistryto control the regioselectivity of the requisite C-H bondtransformation. In symmetrical substrates, mono- or bis-directarylation typically proceedsortho to the directing group viaformation of a five- or six-membered metallacycle. In un-symmetrical substrates, sterics become the controlling factor,resulting in direct arylation occurring predominately at theless hinderedortho position.

Mechanism of C-H Insertion. Mechanistically, theintramolecular and intermolecular direct arylation of arenesis proposed to occur via oxidative addition of the transitionmetal into the aryl halide, followed by one of a number ofpossible key carbon-carbon bond-forming steps (Scheme7): (1) electrophilic aromatic substitution at the metal(SEAr),34-42 (2) a concerted SE3 process,43 (3) a σ-bondmetathesis,38,44,45(4) a Heck-type (or carbometalation) pro-cess either through a formalanti â-hydride elimination orvia isomerization followed by asyn â-hydride elimina-tion,37-40,42,46,47or (5) a C-H bond oxidative addition.44,48-50

While the exact nature of this step has been investigated forsome systems, it should be noted thatthe exact mechanismfor any giVen example depends heaVily on the substrate,transition metal, solVent, base, and ligand used.

Accordingly, this portion of the review will highlightdevelopments in both the intramolecular and intermoleculardirect arylation reactions. Where appropriate, additionalmechanistic discussion will be presented.

2.1. Intermolecular Aryl −Aryl Bond Formation

2.1.1. Direct Arylation via Transition-Metal CascadeReactions Involving Alkenes and Alkynes

2.1.1.1. Alkenes.The direct arylation of aryl halides viaa palladium-catalyzed, norbornene-mediated cascade reactionhas been described by Catellani and co-workers in variousreviews.51-55 In earlier work by Catellani, reaction ofbromobenzene with norbornene in the presence of Pd(PPh3)4

and t-BuOK in anisole at 105°C afforded the hexahy-dromethanotriphenylene (4) in 65% yield (Scheme 8).56

The unusual product was proposed to be a direct conse-quence of the different reactivities of the palladium(0),palladium(II), and palladium(IV) intermediates (Scheme

Scheme 7

Scheme 8


9).52,54 The catalytic cycle is initiated by oxidative additionof palladium(0) into bromobenzene to afford the phenylpal-ladium bromide.Syn insertion of norbornene affords thecis,exo-complex5, which in the absence of asynâ-hydrogenundergoes insertion into an aryl C-H bond to affordpalladacycle6, presumably via electrophilic substitution atthe ortho aromatic carbon. In the presence of an additionalequivalent of bromobenzene,6 undergoes an oxidativeaddition/reductive elimination sequence to afford eitherintermediate8 or 9, likely via a palladium(IV) intermediate,7.54 Finally, cyclization of8 or 9 occurs to give the desiredcyclized product4. The authors have also reported the useof this methodology in the synthesis of other relatedpolycyclic compounds.57,58

Although palladium(IV) species are often presumed to bean intermediate in the aforementioned reaction, there is noexperimental evidence for the oxidative addition of arylhalides to palladium(II) complexes.59 Recently, Echavarrenand co-workers have found that this process may in factproceed without the intermediacy of palladium(IV) com-plexes.59 The authors conducted a computational study todetermine how palladacycles such as6 (Scheme 9) (and28,Scheme 71) react with C(sp2)-X electrophiles to form theC(sp2)-C(sp2) bond that is present in the final compound.DFT calculations were conducted on model complexes toexplore two possible mechanisms (Scheme 10): (1) theoxidative addition of aryl halides to palladacycles to givepalladium(IV) intermediates and (2) a transmetalation-typereaction of arene ligands between a palladacycle and apalladium(II) complex formed by oxidative addition of anaryl halide to palladium(0). Calculations conducted byEchavarren and co-workers indicated that aryl electrophilesreact more easily with unsaturated palladium(0) complexesthan with palladium(II) metallacycles, suggesting that theformation of C(sp2)-C(sp2) bonds in palladium-catalyzedreactions of this type occurs without the intermediacy ofpalladium(IV) complexes. While these results may apply tothis and related processes discussed in this section, theproposed mechanism put forth by the original authors willbe discussed where appropriate.

Catellani has also demonstrated that a terminating Heckcoupling step was possible for her norbornene-mediated,palladium-catalyzed cascade reactions in the presence ofexcess methyl acrylate (Scheme 11).60 Applying these

conditions to 2-iodotoluene in the absence of an additionalcoupling partner afforded an unusual C(sp2)-C(sp3) couplingproduct via an intramolecular benzylic C-H activation(Scheme 12).61

de Meijere reported a similar coupling in which a numberof norbornene-annulated 4-phenyl-9,10-dihydrophenanthrenederivatives could be prepared from a variety of unsubstitutedand para-substituted bromo- and iodobenzenes using Jef-fery’s conditions in the presence of 3 equiv of aryl halide(Scheme 13).62,63 In addition, this methodology could beextended to include other strained norbornene-type alkenessuch as dicyclopentadiene, norbornenol, and norbornenone.64

This palladium-catalyzed, norbornene-mediated couplinghas also been carried out using aryl halides containing anortho substituent in the presence of a coupling partner togenerate norbornene-free biaryl products (Scheme 14).65

While the mechanism is similar to that illustrated in Scheme9, one noteworthy difference is that, in this case, the presenceof an ortho substituent results in the faster reductiveelimination of the palladium(IV) intermedate10 to form an

Scheme 9 Scheme 10

Scheme 11

Scheme 12


aryl-aryl bond instead of the corresponding aryl-norbornylbond. The resulting sterically-hindered complex then expelsnorbornene via retrocarbopalladation to afford the biphenylylcomplex11, which then reacts with the final coupling partner.The authors have subsequently extended the scope of thisreaction to include a large variety of coupling partners suchas olefins,66,67allylic alcohols,65 diphenyl- and alkylphenyl-acetylenes,68 arylboronic acids,69 hydrogen donors,70 andamides71 (Scheme 15).

de Meijere also demonstrated that indene reacts ana-logously to norbornene-type alkenes (Scheme 16).10,62 Sub-sequent studies by Thiemann described a similar triplearylation process using a dihydronaphthalene tricarbonyl-chromium(0) complex under Jeffery’s conditions (Scheme17).72

Other highly strained double-bond-containing systemshave been successfully utilized in palladium-catalyzeddomino processes.73,74 Treatment of the strained hexacyclichydrocarbon12 with iodobenzene and iodobenzene deriva-tives afforded the corresponding propellanes in modest togood yields (Scheme 18). Interestingly, reactions carried outwith 4-iodotoluene were observed to afford products bearinga regiochemical outcome similar to that of products previ-ously reported using norbornene-type systems.

Acyclic alkenes have also been reported in similar pal-ladium-catalyzed cascade arylations.75,76 Reaction ofR,â-unsaturated phenyl sulfones with aryl iodides using Pd(OAc)2

and Ag2CO3 gave 9-(phenylsulfonly)-9,10-dihydrophenan-threnes as the major product along with small amounts ofthe Heck product (Scheme 19). A variety ofâ-substituentson theR,â-unsaturated sulfone were tolerated including alkyl,aryl, and alkenyl substituents. In addition, other electron-poor olefins includingR,â-unsaturated alkyl sulfones, sul-fonamides, phosphine oxides, and phosphonate esters gavesubstantial amounts of the corresponding dihydrophenan-

Scheme 13

Scheme 14

Scheme 15

Scheme 16

Scheme 17


threnes. In contrast, typicalπ-conjugated olefins such asR,â-unsaturated esters and enones almost exclusively affordedthe Heck-type products.

The proposed mechanistic pathway for this palladium-catalyzed cascade arylation reaction is illustrated in Scheme20. Oxidative addition of palladium(0) to iodobenzene in the

presence of Ag2CO3 affords the cationic phenylpalladiumintermediate13. Regioselectivesyn insertion of the alkenethen generates a highly electrophilic sulfonylalkylpalladiumintermediate,14. Unlike the usual behavior of other typesof acyclic alkenes, which afford Heck-type products (viasynâ-hydride elimination), complex14 would evolve fasterthrough an aromatic C-H bond insertion to furnish the five-membered palladacycle15. Support for this process was

recently put forth in a computational study on the mechanismof this domino arylation reaction. The results showed thatvinyl sulfones, unlike enones, are more able to reach thetransition state that leads to the formation of the key five-membered palladacycle.77 The next step then occurs via twopossible mechanisms: (1) an oxidative addition/reductiveelimination pathway via a palladium(IV) palladacycle inter-mediate or (2) a ligand exchange reaction between twopalladium(II) centers. The same sequence of steps results inarylation of the secondortho position, which subsequentlyundergoes aromatic C-H bond activation to afford the seven-membered palladacycle16. Finally, reductive eliminationgenerates the observed dihydrophenanthrene product.

2.1.1.2. Alkynes. The use of alkynes in a tandem,palladium-catalyzed annulation reaction has also been re-ported by Dyker as a new route to substituted phenanthrenes(Scheme 21).78 Various aryl iodides bearing a variety of

electron-withdrawing and electron-donating substituents werecompatible under the reaction conditions, giving mixturesof regioisomeric products.

This reaction was later found by Larock to be highlydependent on the nature of the base used in the reaction. Infact, the product distribution could be drastically alteredsimply by using NaOAc, which selectively afforded 9-alkyli-dene-9H-fluorenes in 25-75% yield (Scheme 22).79,80Vari-

ous electron-withdrawing and electron-donating aryl sub-stituents worked well under the reaction conditions, oftenaffording mixtures ofE/Z products depending on the natureof the aromatic substituents. In addition, suitable alkynepartners for this reaction included those with an aryl groupat one end of the alkyne and another sterically large groupsuch as an aryl ortert-butyl group at the other.

The proposed mechanism for this transformation is illu-strated in Scheme 23. Oxidative addition of palladium(0) tothe aryl iodide followed by alkyne insertion affords a vinylicpalladium(II) species. 1,4-Palladium migration furnishes thearylpalladium(II) intermediate17. Cyclization of17 eithervia an oxidative addition/reductive elimination pathway or

Scheme 18

Scheme 19

Scheme 20

Scheme 21

Scheme 22


by an electrophilic aromatic substitution/reductive eliminationroute then affords the fluorene product.

2.1.2. Directing Group-Assisted Arylation of FunctionalizedAromatic Hydrocarbons

One method by which the regioselectivity of arenearylation can be controlled is through the use of directinggroups. Common directing groups employed for this reactiontypically bear a lone pair of electrons that can coordinate tothe transition-metal catalyst to direct arylation via a five- orsix-membered metallacycle. This section will highlight thecontributions in this area of direct arylation according to thenature of the directing group employed.

2.1.2.1. Phenols.Following Rawal’s report on the in-tramolecular arylation of phenols (Scheme 82), Miura dis-closed a selective intermolecular arylation of 2-phenylphenolsand naphthols. Using a variety of substituted aryl halides inthe presence of Pd(OAc)2 or PdCl2, and Cs2CO3 in DMF at100 °C, the desired mono- or diarylated product could beselectively obtained by varying the amount of aryl iodideand Cs2CO3 used (Scheme 24).81,82

The authors propose that the reaction proceeds via initialoxidative addition of palladium(0) to the aryl iodide, followedby transmetalation of the cesium phenolate to form an aryl-(aryloxido)palladium intermediate,20 (Scheme 25). Coor-dination of the phenolic oxygen to the palladium center in20 is proposed to control the regioselectivity of the resultingC-H bond activation to form intermediate21. Reductiveelimination of 21 then furnishes the desired monoarylatedproduct22. The authors note that use of cesium carbonateas a base was crucial to the success of the reaction since itsrelatively high solubility in DMF is expected to enhance therate of deprotonation, thereby facilitating the transformationof 20 to 21.

These studies have also been extended to the arylation ofnaphthols, phenol, and 2,6-disubstituted phenols. Whilemonoarylation of 1-naphthol occurred selectively to give8-phenyl-1-naphthol (Scheme 26),81,82 use of unsubstitutedphenol was reported to undergo pentaarylation around theoxygen when treated with an excess of aryl bromide (Scheme27).83 Interestingly, 2,6-disubstituted phenols were found toundergo arylation exclusively at theparaposition. For exam-ple, sterically hindered 2,6-di-tert-butylphenol resulted in anumber of 1,1′-biphenyl-4-ols when reacted with various sub-stituted aryl bromides (Scheme 28).84 These compounds werebelieved to arise through electrophilic attack at theparaposition.

A complementary, rhodium-catalyzedortho-selective in-termolecular arylation of phenols has also been reported by

Scheme 23 Scheme 24

Scheme 25

Scheme 26


Bedford (Scheme 29).85,86 Using RhCl(PPh3)3 (5 mol %) asthe catalyst and P(i-Pr)2(OAr) (15 mol %) as the cocatalyst,a variety of 2-substituted phenols could be selectivelyorthoarylated in good yield. The proposed mechanism involvesinitial oxidative addition of Rh(I) to the aryl bromide,followed by coordination of phosphinite andorthometalationof the phenolic moiety of the ligand to provide intermediate22 (Scheme 30). Reductive elimination of theortho-

metalated ligand and the aryl group regenerates the activecatalyst and forms a 2-arylated aryl dialkylphosphiniteintermediate. Transesterification of this intermediate with thestarting phenol then regenerates the cocatalyst and furnishesthe 2-arylated phenol product.

Although these original conditions using RhCl(PPh3)3/P(i-Pr)2(OAr) worked well for 2-substituted phenols, use ofcatalytic [RhCl(cod)]2/P(NMe2)3 was found to give betterresults for phenols lacking anorthosubstituent. For example,treatment of phenol and 4-bromoanisole with [RhCl(cod)]2/P(NMe2)3 afforded a 50:3 ratio of di- to triarylated productsin 62% yield (Scheme 31).86

At the same time, Oi and co-workers independentlyreported a rhodium-catalyzedorthoarylation of phenols witharyl bromides.87 Arylation of a number of substituted phenolswith aryl bromides could be carried out in the presence of[RhCl(cod)]2, HMPT, K2CO3, and Cs2CO3 in toluene at 100°C. In all cases, a mixture of mono- and diarylated productswere obtained in moderate yields (Scheme 32). The authors

suggest a mechanism similar to that proposed by Bedford,in which the reaction proceeds via in situ generation of anarylphosphite intermediate, followed by phosphorus-directedortho metalation and transesterification of the arylatedarylphosphites with the phenol substrate.

2.1.2.2. Arylmethanols.Miura recently demonstrated theutility of an alcohol directing group for the direct arylationof R,R-disubstituted arylmethanols with aryl halides (Scheme33).88,89During the course of their studies, a competing sidereaction was discovered in which tandem palladium-catalyzed C-H and C-C bond cleavage occurred. Thesp2-sp3 C-C bond was cleaved to eject acetone, followedby aryl-aryl coupling.90,91 One particularly interestingexample is the reaction of alcohol23 with 1,2-dibromo-4,5-dimethylbenzene to afford triphenylene in 60% yield (Scheme34).89

Scheme 27

Scheme 28

Scheme 29

Scheme 31

Scheme 32

Scheme 30


2.1.2.3. Ketones.Miura and co-workers92,93 have alsoinvestigated the keto-directed arylation of aryl ketones.94

Reaction of benzyl phenyl ketones with substituted arylbromides in the presence of Pd(PPh3)4 and Cs2CO3 inrefluxing o-xylene afforded various triarylated products inmoderate yields (Scheme 35). This reaction was found to

be highly sensitive to the electronics of both the aryl bromideand phenyl ketone. In particular, use of electron-donatingsubstituents on the aryl bromide were found to slow the rateof arylation. Conversely, electron-withdrawing substituentson the phenyl ketone enhanced the rate ofortho arylation,presumably by the promotion of enolate formation of theR-arylated intermediate24 (Scheme 36). In addition, the useof acetophenone and propyl and butyl phenyl ketone led toa mixture of bothorthoarylation and alkyl arylation products,while ethyl phenyl ketone was reported to undergo arylationexclusively on the alkyl moiety.95

Mechanistically, the authors propose that deprotonationof the R-arylated intermediate2496 occurs to afford thecesium enolate25 (Scheme 36). Subsequent coordinationof the enolate oxygen to the arylpalladium halide, fol-lowed byortho palladation gives the diarylpalladium inter-mediate26. Reductive elimination of26 and enolate proto-nation then generate the biaryl product27, which under-goes the same sequence of steps for the secondorthoarylation.92

While the majority of transition-metal-catalyzed directarylation reactions of arenes involve the use of aryl halidesor pseudohalides as the coupling partner, several groups haverecently reported the direct arylation of arene C-H bondsusing aryl organometallic compounds. An interesting ex-ample of this was reported by Kakiuchi, who described a

ruthenium-catalyzed arylation of aromatic ketones usingarylboronic esters (Scheme 37).97,98 The reaction of 1 equivof 2′-methylacetophenone with 1 equiv of the phenylbor-onic ester using RuH2(CO)(PPh3)3 as the catalyst in re-fluxing toluene gave theortho-phenylated product in 47%yield. In addition, a nearly equivalent amount of alco-hol derived from the reduction of the starting ketonewas obtained as a byproduct. When a 2-fold excess of theketone was employed, the phenylated product was obtainedin 82% yield (based on the phenylboronic ester) (Scheme37).98 Based on these observations, the authors proposethat the mechanism likely proceeds via a ruthenium-catalyzedortho-hydride abstraction, followed by reduction of theketone carbonyl. The authors later found that this undesiredreduction of the aromatic ketone could be surpressed by theaddition of a hydride scavenger such as pinacolone.

The scope of the reaction was next examined using theoptimized reaction conditions. While acetophenone andisopropyl phenyl ketone furnished the corresponding diary-lated ketone as the major product, use of the bulkiertert-butyl phenyl ketone afforded theortho-monoarylated ketoneexclusively in 76% yield (Scheme 38). It is suggested thatthe large steric repulsion between thetert-butyl group andthe phenyl group introduced at theortho position inhibitsthe second C-H bond cleavage.

Scheme 33

Scheme 34

Scheme 36

Scheme 37

Scheme 38

Scheme 35


The reaction can be applied to various electron-rich andelectron-poor aromatic ketones, including functionalizedacetophenones and acetonaphthones. High yields of productswere obtained, and the electronic nature of the substituenton the aromatic ring did not greatly affect the reactivity ofthe reaction.

Fused aromatic ketones showed significant reactivity inthis reaction. Excellent yields of products were obtained forR-tetralone, 2,2-dimethyl-R-tetralone, and 1-benzosuberone(Scheme 39). Various electron-rich, electron-poor, and

sterically-hindered arylboronic esters were reacted with1-benzosuberone to give the corresponding products inexcellent yields.

The authors conducted several labeling experiments to gaininsight into the reaction mechanism. Intermolecular andintramolecular competition reactions were conducted asshown in Schemes 40 and 41, respectively. The authors

suggest that if the C-H bond cleavage proceeds withoutcoordination of the ketone carbonyl group, thekH/kD valuesfor both the intra- and intermolecular competitive reactionsshould be nearly the same. On the other hand, if the ketonecarbonyl coordinates to the ruthenium prior to C-H bondcleavage, thekH/kD values should be different. The kinetic

isotope effects for the intermolecular competitive reactions(kH/kD ) 1.06 and 1.09) were different from those for theintramolecular competition (kH/kD ) 1.41 and 1.49), sup-porting the proposal that the ketone carbonyl group coordi-nates to the ruthenium prior to C-H bond cleavage.

The proposed mechanism begins with coordination of theketone to ruthenium, followed by cleavage of the C-H bondto afford a five-membered ruthenacycle (Scheme 42). Ad-

dition of Ru-H to the pinacolone carbonyl results in analkoxyruthenium intermediate. Transmetalation between thealkoxyruthenium intermediate and the arylboranate thenaffords the diarylruthenium intermediate and a trialkoxy-borane, which was detected by1H and 11B NMR and GC/MS spectrometry. Reductive elimination furnishes the biarylproduct and regenerates the active catalyst.

2.1.2.4. Benzaldehyde and Phenylacetaldehydes.Morerecently, the use of aldehydes as directing groups for thepalladium-catalyzed arylation of arenes has also beenreported. Using Pd(OAc)2 and a bulky electron-richN-heterocyclic carbene ligand, arylation of a variety of ben-zaldehyde derivatives could be carried out with a large rangeof electron-rich and electron-poor aryl halides in good toexcellent yields.99 In addition, the authors showed that arylchlorides can also be used to achieve selective monoarylation

Scheme 41

Scheme 42

Scheme 39

Scheme 40


in contrast to the diarylated products typically obtained witharyl bromides (Scheme 43).

The palladium-catalyzed arylation of a phenylacetaldehydewith bromobenzene has also been studied by Miura (Scheme44).95 In this case, only theortho-monoarylated compoundwas obtained in a modest 44% yield.

2.1.2.5. Amides.Following the successful arylation ofaromatic ketones and phenols, Miura utilized this methodol-ogy for the palladium-catalyzed arylation of benzanilides.100

In this investigation, benzanilides were found to efficientlyundergo diarylation with aryl triflates and bromides in goodto excellent yields (Scheme 45). Importantly, neither the

N-arylated product nor the arylatedN-phenyl-substitutedregioisomer was observed. The authors propose a mechanismsimilar to that reported for the corresponding phenolic andketone systems (see sections 2.1.2.1 and 2.1.2.3, respec-tively), whereby in this instance, coordination of the amidateion to the intermediary arylpalladium species would occuras the key step.

Sanford and co-workers101 recently reported a palladium-catalyzed oxidative C-H activation/arylation of amide

derivatives using hypervalent iodine compounds as theoxidizing arylation reagent (Scheme 46). One advantage ofthis highly practical reaction is that it does not require theuse of strong bases or expensive ligands, and can beconducted without any precautions with regard to theexclusion of air and moisture. The mechanism is believedto involve a Pd(II)/Pd(IV) catalytic cycle and is describedin more detail in section 2.1.2.7.

An interesting direct arylation side reaction was observedduring the palladium-catalyzed synthesis of pyridones fromo-bromoarylcarboxamides.102 While the desired product wasobtained in only 23% yield, the competing direct arylationside product was isolated in 34% yield. The final arylationis believed to be directed by the amide functionality via afive-membered palladacycle intermediate (Scheme 47).

Scheme 43 Scheme 46

Scheme 47

Scheme 44

Scheme 45


2.1.2.6. Imines.Imines have also been successfully utilizedas directing groups for the ruthenium-catalyzed directorthoarylation of aromatic imines with a variety of aryl and alkenylhalides.103 Interestingly, the size of the alkyl group on theimino moiety was found to affect the ratio of mono- todiphenylated product (Scheme 48). The authors propose that

this phenomenon is due to steric interactions between thealkyl group on the imine moiety and the newly introducedphenyl group, thereby preventing imine rotation and subse-quent arylation. Support for this proposal was obtainedthrough scope investigations in which an ethyl group on theimino moiety was also observed to give a similar ratio ofmono- to diphenylated products compared to the methylanalogue, while use of hydrogen on the imino moiety wasfound to undergo diphenylation exclusively. Additional scopestudies also revealed thatmeta-substituted imines underwentselective monoarylation at the less hinderedortho position(Scheme 49).

Mechanistically, the reaction is proposed to occur viainitial oxidative addition of Ru(II) to the aryl bromide(Scheme 50). The resulting arylruthenium(IV) complexcoordinates to the imino group to afford an arylated ruth-enacycle intermediate, which undergoes subsequent reductiveelimination to furnish theortho-arylated product.

A ruthenium-catalyzed arylation using aryl chlorides hasalso been achieved using phosphine oxides as preligands.104

Reaction of an imine with an aryl chloride in the presenceof [RuCl2(p-cymene)]2 and an adamantyl-substituted second-ary phosphine oxide afforded the desired aryl imine, whichupon hydrolysis afforded the monoarylated ketone in goodyield (Scheme 51). Both electron-rich and electron-poor arylchlorides were tolerated in this reaction, and a wide varietyof functional groups were compatible including enolizableketones, nitriles, and esters.

Miura and co-workers105 have also demonstrated the utilityof imines as directing groups for the rhodium-catalyzedorthoarylation of benzophenone imine with sodium tetraphenylbo-rate (Scheme 52). In this example, a mixture of mono- anddiphenylated products were obtained in addition to the

reduced aminodiphenylmethane byproduct. The formationof significant amounts of this byproduct suggests that thebenzophenone imine acts as a hydride scavenger in thereaction. The authors propose that this most likely occursvia initial coordination of the benzophenone imine nitrogento the phenylrhodium intermediate, followed byorthorhodation to afford a five-membered rhodacycle intermediate(Scheme 53). Subsequent reductive elimination generates themonophenylated product and a rhodium hydride species,which then reduces the benzophenone imine in the presenceof a proton donor to regenerate the active catalyst.

2.1.2.7. Pyridines and Quinolines.In addition to thedirect arylation of aromatic pyrrolidinones and oxazolidi-nones described in section 2.1.2.5, Sanford has demonstratedthat pyridines and quinolines are effective directing groupsfor palladium-catalyzed arene arylation using hypervalentiodine arylating agents.101 Under these conditions, a numberof functionalized pyridines could be used to direct monoary-lation onto a variety of both electron-rich and electron-poor

Scheme 50

Scheme 51

Scheme 52

Scheme 48

Scheme 49


arenes (Scheme 54). Interestingly, arenes bearing a coordi-nating group at the 3′-position (e.g., 3′-acetyl) exclus-ively afforded a single regioisomeric product in whicharylation occurred at the less sterically-hindered 6′-position.These findings suggest that the regioselectivity of C-Hactivation in this system is predominantly controlled by stericeffects.

Selective transfer of an aryl group from a mixed hyper-valent iodine reagent has also been achieved using [MesIAr]-BF4. In this case, the bulky Mes group acts as a dummyligand, resulting in selective transfer of the potentially moreprecious arene component (Scheme 55). Use of hypervalentiodine arylating agents proved crucial to the success of thereaction since all attempts to employ alternative arylating

agents such as PhI or PhOTf resulted in less than 1% of thedesired phenylated product.

On the basis of experimental evidence, the authorsproposed a mechanism in which initial C-H activationoccurs to form a cyclometalated palladium(II) intermediate,followed by either: (1) oxidation of palladium(II) to palla-dium(IV) by [Ph2I]BF4 followed by subsequent C-C bondformation via reductive elimination (Scheme 56), or (2) direct

electrophilic cleavage of the palladium(II)-carbon bond by[Ph2I]BF4 (without changing the oxidation state of the metal).

Daugulis also reported a palladium-catalyzed direct ary-lation using a pyridine moiety as a directing group (Scheme57).106 In the presence of excess aryl iodide, 2-phenylpyri-

dine and 7,8-benzoquinoline could be selectively monoary-lated in good yield. It was also shown that the diarylatedproduct could be obtained after prolonged reaction times.The authors speculate that a Pd(0)-Pd(II)-Pd(IV) catalyticcycle is likely involved in the reaction.

Recently, the same group disclosed a highly regioselectivedirect arylation of carboxylic amides possessing a directingaminoquinoline group (Scheme 58).107 The reaction wascarried out using only 0.1 mol % palladium. Remarkably,the iodide on the benzamide was compatible under thereaction conditions. In addition, similar substrates whereinthe position of the carbonyl is inverted afforded themonoarylated product in 81% yield (Scheme 58).

An analogous ruthenium-catalyzed 2′-arylation of 2-aryl-pyridines has also been reported by Oi (Scheme 59).108

Although a mixture of mono- and diarylated products wereobtained when 2-phenylpyridine was treated with 1 equivof bromobenzene in the presence of [RuCl2(η6-C6H6)]2, PPh3,

Scheme 53

Scheme 54

Scheme 55

Scheme 56

Scheme 57


and K2CO3 in NMP at 120°C, use of 3 equiv of bromoben-zene could be used to exclusively afford the diarylatedproduct in 77% yield. As observed in Sanford’s system,monoarylated products at the less sterically hindered positionwere exclusively obtained for 2′- or 3′-substituted arylpy-ridines. A variety of substituted aryl bromides were toleratedunder these conditions to give the desired products in goodyields. Mechanistically, the authors propose that the reactionproceeds via a pathway analogous to theortho arylation ofaryl imines (Scheme 50).

Ackermann subsequently reported a similar ruthenium-catalyzed coupling to include aryl chlorides and aryl tosy-lates.104,109 In this system the reaction was found to becompatible with a wide variety of electron-rich and electron-poor functional groups. Notably, aryl chlorides gave rise todoubly arylated products, while aryl tosylates selectivelygenerated monoarylated products (Scheme 60).

While most methods of direct arylation employ the useof aryl halides, Oi and co-workers have reported a rhodium-catalyzed direct arylation of pyridylarenes using arylstan-nanes (Scheme 61).110 Under these conditions, a variety ofarylpyridines could be selectively arylated in good yield atthe 2′-position. The mechanism of this transformation isbelieved to occur via nitrogen-directed oxidative addition ofa low-valent rhodium complex to theortho C-H bond ofthe phenyl ring, followed by phenylation with tetraphenyl-stannane.

2.1.2.8. Oxazolines, Imidazolines, and Pyrazoles.Vari-ous nitrogen-containing five-membered heterocycles havebeen employed as directing groups in intermolecular directarylation reactions. Oi and Inoue reported a selectiveorthoarylation of 2-arylimidazolines with aryl halides in thepresence of a ruthenium(II)-phosphine complex (Scheme62).111 While the reaction of 2-phenylimidazoline with 1.2

equiv of bromobenzene using [RuCl2(η6-C6H6)]2 gave themono- and diarylated products in a 64% yield and in a31:69 ratio, exclusive formation of the diarylated productcould be achieved in 90% yield using 2.5 equiv of bro-mobenzene. Furthermore, the reaction of variousN-substi-tuted derivatives, which are expected to block the secondcoupling reaction, were found to preferentially give themonoarylated products. In addition, anN-tosyl derivativefailed to give any product, presumably due to the effects ofthe strong electron-withdrawing tosyl group, which is thoughtto decrease the ability of the imidazoline nitrogen tocoordinate to the ruthenium complex.

The authors have also applied this method to the directarylation of 2-aryloxazolines (Scheme 63).111 The reactionof 2-phenyl-2-oxazoline with a slight excess of bromoben-zene afforded a mixture of mono- and diarylated productsin 60% yield. The preferential formation of the diarylatedproduct was further enhanced when 2.5 equiv of bromoben-zene was used, affording the product in quantitive yield. The

Scheme 58

Scheme 59

Scheme 60

Scheme 61

Scheme 62


influence of the oxazoline ring substitutents on the mono-and diarylated product distribution was examined using 5,5-dimethyl-2-phenyl-2-oxazoline and 4,4-dimethyl-2-phenyl-2-oxazoline. Whilegem-dimethyl substitution at the 5-po-sition had no effect on the product yield or distribution, thesame substituents at the 4-position exclusively afforded themonoarylated product, albeit in a low 11% yield. The authorspropose that the low yield for this example is due to theinability of the sterically-encumbered nitrogen to coordinateto the ruthenium complex.

The following two steps are believed to play some part inthe catalytic cycle: (1) oxidative addition of the aryl halideto the ruthenium complex to furnish an arylrutheniumintermediate, and (2) oxazoline- or imidazoline-directedorthoruthenation of the aromatic ring. Two possible mechanismsare depicted in Scheme 64. In pathway A, oxidative additionof the aryl halide to a ruthenium(II) complex generates an

arylruthenium intermediate.Ortho ruthenation of the aryl-oxazoline or arylimidazoline with the arylruthenium inter-mediate then furnishes a ruthenacycle which undergoesreductive elimination to afford the desired product and toregenerate the active catalyst. In pathway B, the ruthena-cycle is formed from the reaction of the aryloxazoline orarylimidazoline with a ruthenium(II) complex. Oxidativeaddition of the aryl halide affords a second ruthena-cycle which undergoes reductive elimination to furnish thedesired product. On the basis of previous literature precedent,the authors propose that this reaction likely proceeds viapathway B.

Oxazoline and pyrazole have also been efficiently usedas directing groups in direct arylation reactions with arylchlorides and tosylates. In these examples, a highly activeruthenium catalyst derived from an air-stable secondarydiaminophosphine oxide was used.109 Various electron-richand electron-poor aryl tosylates with a diverse range offunctional groups including alkenes, esters, nitriles, andketones were compatible under the reaction conditions,affording high yields of the expected products (Scheme 65).

Both aryl chlorides and aryl tosylates were used in thedirect arylation of a pyrazole derivative. Interestingly, arylchlorides gave rise to a doubly arylated product, while aryltosylates formed the monoarylated product selectively (Scheme66).

In addition, pyrazole has also been reported as an effec-tive directing group in the palladium-catalyzed direct ary-lation of 1-phenylpyrazole using aryl iodides (Scheme67).106

2.1.2.9. Anilides. The preparation ofortho-substitutedanilides via a palladium-catalyzed direct arylation hasrecently been reported by Daugulis (Scheme 68).112 Thismethod demonstrated a wide functional group tolerance onboth the anilide and aryl iodide moieties. Again, monoary-lated products were exclusively obtained whenortho- ormeta-substituted anilides were used in the reaction.

2.1.2.10. Ethers.Fagnou recently reported the directarylation of an aryl ether (Scheme 69).28 A broad range ofelectron-rich and electron-poor aryl bromides and chlorides

Scheme 63

Scheme 64

Scheme 65


could be used in the presence of 10 equiv of benzodioxoleto give high yields of the coupled products. Sterically-encumbered aryl bromides could also be used to afford thedesired product in good yield. Unexpectedly, the use of aryliodides under the reaction conditions was found to insteadgive homocoupled products.

2.1.2.11. Alkyls. Dyker reported a procedure for thesynthesis of annulated pyrans and furans via a palladium-catalyzed domino coupling ofo-iodoanisoles.113-116 In thisunusual domino coupling, three molecules of 2-iodoanisolecombine to selectively form the substituted dibenzopyran in90% yield (Scheme 70). The proposed mechanism involvesan initial oxidative addition/cyclometalation sequence thatresults in the formation of a five-membered oxapalladacycle,28, which subsequently undergoes oxidative addition with a

second equivalent of 2-iodoanisole to afford a palladium-(IV) intermediate (Scheme 71). Reductive elimination of thispalladium(IV) intermediate to generate the first aryl-arylbond, followed by a secondortho cyclometalation andoxidative addition of a third equivalent of 2-iodoanisole thenforms a second palladium(IV) intermediate. Finally, reductive

Scheme 66

Scheme 67

Scheme 68

Scheme 69

Scheme 70

Scheme 71


elimination and subsequent cyclometalation/reductive elimi-nation result in the dibenzopyran product. Alternatively, atransmetalation-type exchange of aryl ligands between dif-ferent palladium(II) centers is possible (Scheme 10).59

The same authors have also demonstrated thattert-butyl-substituted arenes undergo C-H activation at the sp3-hybridized center followed by direct arylation to afford thebenzocyclobutyl product (Scheme 72).117 Although this

pathway involves formation of a strained four-memberedring, the authors propose that carbocycle formation may bedriven in this case by the steric interaction between the arylsubstituent and thegem-dimethyl group.118

2.1.2.12. Phospines.More recently, Hartwig and co-workers developed conditions for the preparation of an air-stable, sterically-hindered ferrocenyldialkylphosphine usedfor palladium-catalyzed C-C, C-N, and C-O cross-cou-pling reactions.119 Treatment of (di-tert-butylphosphino)-ferrocene with Pd(OAc)2 and sodiumtert-butoxide in neatphenyl chloride at 95-110°C afforded the pentaphenylfer-rocenyl ligand in 90% yield by NMR spectroscopy (Scheme73).

2.1.3. Direct Arylation of Aromatic Hydrocarbons in theAbsence of a Directing Group

While reports of direct arylation of unfunctionalizedaromatics are uncommon, Dyker reported the arylation ofazulene, an aromatic hydrocarbon that exhibits an increasedreactivity due to its dipolar nature (Scheme 74).120 Under

palladium-catalyzed conditions, azulene is arylated regio-selectively at the electron-rich C-1 position. Several mecha-nistic experiments suggest a process involving electrophilicaromatic substitution of azulene with the in situ generatedarylpalladium halide. Typical yields for this process werelow, exemplifying the difficulty associated with palladium-catalyzed nondirected intermolecular arylation. Extension ofthis arylation protocol to the arylation of other polycyclicaromatic hydrocarbons including anthracene, phenanthrene,and pyrene were not successful.

Iridium has also been used for the direct arylation of areneC-H bonds in the absence of a directing group.121 In thisstudy, various aryl iodides were reacted with benzene in thepresence of [Cp*IrHCl]2 (5-10 mol %) at 80°C to affordthe corresponding biaryl products in moderate yields (Scheme75).

The authors propose that the reaction proceeds via initialbase-mediated reduction of Cp*Ir(III) to Cp*Ir(II), followedby electron transfer from Cp*Ir(II) to the aryl iodide to affordan aryl iodide radical anion and the starting Cp*Ir(III)catalyst. Subsequent elimination of I- from the radical anionfurnishes an aryl radical which can then react with benzeneto give the biaryl product.

Miura and Dyker have developed a procedure for thesynthesis of pentaarylated cyclopentadienes via arylation offive-membered aromatic-containing metallocenes.122-124 Re-action of zirconocene dichloride with bromobenzene in thepresence of Pd(OAc)2, PPh3, and Cs2CO3 in DMF at 130°Cafforded the 1,2,3,4,5-pentaphenyl-1,3-cyclopentadiene in70% yield (Scheme 76). While titanocene dichloride and

nickelocene afforded>60% yields of product, cobaltoceneand ferrocene gave low yields (23% and<1%, respectively)of the desired product. Both electron-rich and electron-pooraryl bromides were found to be compatible under the reactionconditions. In addition, use of tri-tert-butylphosphine wasshown to enhance the efficiency of the reaction with certainaryl bromides. Mechanistically, the authors propose thatwhile the first arylation is considered to involve transmeta-lation between the metallocene and the phenylpalladiumhalide intermediate, subsequent arylations likely occur withthe corresponding monoarylated cyclopentadiene moiety via

Scheme 72

Scheme 73

Scheme 74

Scheme 75

Scheme 76


a base-mediated process that resembles arylation reactionsof other soft nucleophiles.125 This method was also extendedto the palladium-catalyzed arylation of cyclopentadiene witharyl bromides. In this case, deprotonation of cyclopentadienein the presence of base affords a relatively stable cyclopen-tadienyl anion, which can then undergo transmetalation andsubsequent arylation.

A direct arylation of electron-deficient perfluorobenzeneswith various aryl halides using Pd(OAc)2 and P(t-Bu)2Me-HBF4 was recently reported (Scheme 77).126 Aryl chlorides,

bromides, and iodides all afforded the desired biaryl products,with aryl bromides being the most effective. Higher yieldsof products were obtained with aryl iodides when AgOTfwas added. Arylation of pentafluorobenzene with a numberof arylbromides with varying electron-donating and electron-withdrawing substituents afforded the desired biaryl productsin good to excellent yields.

In addition, these conditions could be used for the selectivemonoarylation of mono-, di-, tri-, and tetrafluorobenzenesusing 4-bromotoluene (Scheme 78). Interestingly, arylation

of 1,3-difluorobenzene occurred selectively at the C-H bondbetween the two fluorine atoms in 85% yield.

This reaction exhibits reactivity opposite that of SEArreactions. Further computational and experimental studiesdetermined that the key C-H bond functionalization stepoccurs via a concerted arene metalation and proton abstrac-tion. The proposed mechanism is illustrated in Scheme 79

and is believed to occur via proton abstraction by a ligatedbicarbonate ion (mechanism B). Alternatively, it is alsopossible that proton abstraction could occur with a ligatedBr ion as well (mechanism A).

2.2. Intramolecular Aryl −Aryl Bond Formation

Intramolecular direct arylation reactions have been exten-sively utilized in organic synthesis as a route to numerouscomplex polycyclic ring systems. This section of the reviewwill focus on the developments of this important reactionwith regard to recent mechanistic studies and the applicationof this methodology toward a variety of natural products andsynthetically interesting materials.

2.2.1. Scope and Limitations

One of the earliest examples of intramolecular directarylation was reported by Ames in the early 1980s.127 In thisseminal study, a variety of functionalized dibenzofurans wereprepared by treating the corresponding 2-bromophenyl phen-yl ethers in DMA at 170°C in the presence of Pd(OAc)2

and Na2CO3 (Scheme 80). Electron-donating and electron-withdrawing substituents were tolerated under the reactionconditions to afford the desired products in good yields. Inaddition, reactions using (iodophenyl)phenylamine and iodo-benzophenone were found to yield the corresponding car-bazole and fluorenone products in high yields.128

The authors extended this method to the synthesis of othercyclic compounds by preparing substrates with varyinglinkages between the two aryl groups (CH2O, NRCO,SO2NR) and subjecting these compounds to their palladium-catalyzed direct arylation conditions (Scheme 81).128 In thesecases however, preparation of the desired fused six-membered ring products occurred in low yields.

Scheme 77

Scheme 78

Scheme 79


The intramolecular arylation of phenolates using Her-rmann’s catalyst and Cs2CO3 in DMA has been reported byRawal (Scheme 82).129 Under these conditions, a variety ofbiaryl compounds containing various linkages between thetwo aryl groups were obtained in good to excellent yields.

Selective direct arylation for this system was observed tooccurortho to the phenol functionality. For substrates bearinganorthoblocking group, cyclization also occurred, althoughin this instance cyclization occurredpara to the phenolfunctionality. The reaction was also found to be sensitiveto steric effects, since bulky aryl iodides underwent cycliza-tion preferentially at the less hindered 4-position (Scheme83).

The proposed mechanism for this reaction begins with theoxidative addition of palladium to the aryl halide to affordan arylpalladium halide intermediate (Scheme 84).Orthonucleophilic attack of the palladium(II) species by thephenolate, followed by tautomerization, generates a dia-

rylpalladium species which undergoes reductive eliminationto afford the desired product. The authors suggest that theimproved yields in this system are due to the increasedelectron density on the aromatic ring in the phenolate, therebymaking it more reactive in the coupling reaction. In fact,the importance of the free hydroxyl group to the success of

Scheme 80

Scheme 81

Scheme 82

Scheme 83

Scheme 84


the reaction was demonstrated by a comparison study inwhich a substrate containing a methyl ether instead of aphenol was found to afford only a 10% yield of the desired4-cyclized product along with recovered starting material(Scheme 85).

Recently, Fagnou reported extensive investigations intothe scope and limitations of the intramolecular directarylation reaction of arenes.130 Their improved reactionconditions resulted in enhanced catalytic activity using verylow catalyst loadings for previously reported unreactive andpoorly reactive substrates. Formation of the desired biarylwas achieved in 96% yield using 0.1 mol % Pd(OAc)2, ligand31, and K2CO3 in DMA at 145°C (Scheme 86). In addition

to the expected biaryl product, a small amount of hydrode-bromination byproduct was also observed. This method wasalso effective for the preparation of more challenging seven-membered ring products. In this particular example, use ofthe electron-deficient ligand32 significantly enhanced thereaction, affording the biaryl product in 96% yield. Theauthors suggest the enhanced activity might be due to thefacile dissociation of the bulky, electron-poor ligand fromthe palladium metal, thereby allowing for facile coordinationof the arene.

A variety of six-membered ring biaryl compounds wereprepared bearing both electron-donating and electron-withdrawing substituents in excellent yields (Scheme 87).Furthermore, alkyl- and nitrogen-containing tethers weretolerated, but required higher catalyst loadings to ensurecomplete conversion.

While the aforementioned catalytic system proved ex-tremely effective for the direct arylation of aryl bromides,

poor yields of the cyclized products or no reaction at all wasobserved for aryl chlorides. To address this issue, Fagnou131

developed new conditions employing electron-richN-het-erocyclic carbene (NHC) ligands.132 Using 1-3 mol %catalyst33 and K2CO3 in DMA at 130 °C, a variety offunctionalized five- and six-membered rings could beprepared in excellent yields with varying tethers that includedether, amine, amide, and alkyl functionalities (Scheme 88).

The same authors subsequently demonstrated thatPd(OH)2/C is also very effective for the intramolecular directarylation of aryl iodides and aryl bromides to form five- andsix-membered hetero- and carbocyclic ring systems (Scheme89).28,133

Investigations were also conducted to ascertain the natureof the active catalyst. Treatment of a solid support substratewith Pd(OH)2/C, followed by cleavage with TFA, gave thedesired product in 100% conversion (Scheme 90). This resultindicates that a soluble catalyst species had leached intosolution, since it is not possible for two solid phases tointeract. In a second test, a homogeneous aryl iodide wastreated with Pd(OH)2/C in the presence of a solid-phase thiolscavenger resin. In this case, no reaction occurred, suggestinga homogeneous active catalyst was operative since this

Scheme 85

Scheme 86

Scheme 87

Scheme 88


scavenger resin would be expected to only remove thehomogeneous catalyst present in the reaction.

More recently, Fagnou developed an efficient generalcatalyst system for the intramolecular direct aryation of abroad scope for aryl chlorides, bromides, and iodides(Scheme 91) to generate numerous five- and six-memberedcarbo- and heterocyclic biaryl compounds.28 A variety ofether-, amine-, amide-, alkyl-, and alkenyl-based tethers werealso tolerated. In addition, a variety of electron-withdrawingand electron-donating substituents were compatible on botharyl moieties, affording the desired products in excellentyields and high regioselectivity. Furthermore, this catalystsystem also allowed for the direct arylation of more sterically-demanding substrates (Scheme 92).

Although these conditions worked well for aryl bromidesand chlorides, aryl iodides were found to react poorly(Scheme 93). Subsequent studies in which the addition of 1equiv of KI retarded the direct arylation of an aryl bromideled the authors to suggest that the iodide anions generatedduring the course of the reaction act as catalyst inhibitors.

This problem was overcome by the addition of Ag2CO3 tothe catalyst system. Using these slightly modified conditions,a diverse range of biaryl compounds were prepared fromthe corresponding aryl iodides in high yield.

Since the use of aryl iodides is common in cross-couplingreactions, it is unlikely that the accumulation of iodide inthe reaction mixture inhibits the oxidative addition orreductive elimination steps. Instead, the authors suggest thatiodide inhibition occurs during the arylation step by bindingto the palladium, forming a coordinatively saturated andtherefore unreactive palladium species (Scheme 94).

This methodology was further extended to a tandem Heck/direct arylation reaction sequence.134 Substrates containingboth a bromide and a chloride functionality were reacted witha Heck acceptor using Pd(OAc)2 (10 mol %), Pt-Bu3-HBF4

(20 mol %), and K2CO3 in DMA at 130 °C. Under theseconditions, a variety of substituted biaryl products could beprepared in good yields (Scheme 95). In addition, the reaction

Scheme 89

Scheme 90

Scheme 91

Scheme 92

Scheme 93

Scheme 94


was compatible with a number of acrylates and other alkenes.Further extension of these conditions allowed for an interest-ing tandem-sequential Heck/direct arylation/hydrogenationsequence by replacing the nitrogen atmosphere of thecompleted reaction with hydrogen (Scheme 96).

Fagnou subsequently conducted a series of experimentsaimed at providing insight into palladium-catalyzed directarylation reactions.28 Competition experiments depicted inScheme 97 were carried out to determine whether the catalystwould react preferentially with a more electron-poor or

electron-rich arene. In both cases, a small selectivity wasobserved with preference for the more electron-rich arene,although this argument assumes that the reaction occursunder Curtin-Hammett conditions (i.e., that amide rotationis fast compared to the rate of direct arylation).

In addition, while a primary kinetic isotope effect of 3.5was reported under the conditions described in Scheme 87,direct arylation of a simple unsubstituted aryl bromide re-sulted in a primary kinetic isotope effect of 4.25 (Scheme98).

These results exclude an electrophilic aromatic substitutionpathway since this type of reaction usually does not exhibita kinetic isotope effect. The authors rationalize the observedprimary kinetic isotope effect by comparing the relative ratesof coordination of the arene to giveπ,η1 and/orπ,η2 speciesfrom the corresponding palladium(II) arene intermediate (k1

and k-1) to the rate of deprotonation (k2) (Scheme 99). Afast and reversiblek1 andk-1 compared tok2 would makek2

kinetically significant, thereby resulting in a primary kineticisotope effect. Two possible pathways may exist under thesecircumstances: (1) a concerted SE3 process in which anexternal base deprotonates the arene at the same time asPd-C bond formation, or (2) aσ-bond metathesis pathwaywhere an anionic ligand on the palladium removes the proton.As well, the small electronic bias observed for the competionreaction may suggest the absence of a cationic areniumintermediate in the rate-determining step, which furthersupports the aforementioned concerted Pd-C bond forma-tion/C-H bond cleavage processes.

At the same time, Echavarren independently conductedexperiments and carried out computational studies to gaininsight into the mechanism of this direct arylation reaction.29

Competition experiments were preformed on substrateswhereby the aryl bromide could react with either a substitutedor an unsubstituted arene (Scheme 100). In this study, thesubstrates used contained an alkyl tether between the twoaryl groups to minimize steric and/or electronic bias in thereaction. Since small amounts of phenanthrenes were ob-served in the reaction, the crude mixtures were treated withDDQ to fully convert the remainder of the cyclized productsto the corresponding phenanthrenes to facilitate the measure-ment of the ratio of regioisomers.

These studies by Echavarren found a trend different fromthat of Fagnou’s experiment, in that electron-deficientaromatics were slightly favored over electron-rich ones,although this electronic bias was very small regardless ofthe electronic nature of the substituent (for example, R)OMe, CF3, and Cl). Additional studies found that reactionwith R ) 3,4,5-F3 resulted in almost exclusive coupling atthe trifluorophenyl ring (25:1), which is not consistent withan electrophilic aromatic substitution reaction. Furthermore,studies using a deuterated substrate gave an isotope effect(kH/kD) of 5 under the reaction conditions, andkH/kD ) 6.7when run in DMF at 100°C.

On the basis of these experimental studies along withcorroborating computational findings, the authors concluded

Scheme 95

Scheme 96

Scheme 97

Scheme 98


that the palladium-catalyzed arylation does not involve anelectrophilic aromatic substitution. Instead, the authorsproposed a mechanism whereby proton abstraction bycarbonate or a related ligand (but not bromide according tocomputational studies) more likely occurs.

Harayama has also reported extensive studies on pal-ladium-catalyzed intramolecular direct arylation reactions andtheir application toward the synthesis of numerous naturalproducts (see section 2.2.2.1).135 In the early stage ofdevelopment, stoichiometric Pd(OAc)2 was typically requiredin this intramolecular reaction for the coupling of aryliodides, bromides, and triflates. However, the authors foundthat in several cases, only 30 mol % Pd(OAc)2 was requiredto afford the cyclized product in good yield (Scheme101).136,137

Subsequent studies led to the development of improvedconditions that allowed for the coupling of aryl iodides,bromides, and triflates using catalytic palladium (eq 1,Scheme 102).138-140 While these conditions worked well foroxy-substituted haloarenes (eq 2, Scheme 102), extensionto oxy-substituted aryl triflates afforded poor yields of thedesired product. Further studies by the authors have since

found that use of similar conditions with DBU as thebase proved effective for these oxy-substituted aryl tri-flates.141

The cyclization of substrates containing nitrogen in a ringwas also reported.142-144 Six-membered tetrahydroquinolinegave an excellent yield of the desired tetracyclic product(Scheme 103), while use of the five-membered dihydroindolegave a low yield of the desired product under similarconditions. An alternative and higher yielding route to thesame product was achieved using the corresponding substratecontaining the iodide on the dihydroindole moiety.

This methodology has also been utilized for the regiose-lective synthesis of benzonaphthazepines (Scheme 104).145,146

Substrates containing an unsubstituted naphthyl moietyunderwent selective cyclization at the 8-, rather than the2-position. The authors propose a mechanism involvingoxidative addition of palladium(0) to the aryl bromide,followed by amine coordination to palladium(II) and regio-selective electrophilic substitution of palladium(II) at the8-position. Subsequent reductive elimination then affords theobserved product. Other substituted naphthyl rings alsoshowed the same regioselectivity except when bulky sub-stituents such as a 7-isopropoxynaphthalene was used.

Scheme 99

Scheme 100

Scheme 101

Scheme 102


Cyclization in this latter case afforded the 2-cyclized productexclusively.

Domınguez has described the synthesis of pyrazolophenan-thridines via a palladium-catalyzed direct arylation of aryl-substituted pyrazoles (Scheme 105).147 The resulting cycliza-tion using Pd(OAc)2, K2CO3, LiCl, andn-Bu4Br in DMF at110 °C in a sealed tube generated a number of pyrazolo-phenanthridines in 42-65% yields.

A synthesis of carbazoles via a two-step process involvinga palladium-catalyzed amination/intramolecular direct ary-lation reaction sequence has also been reported (Scheme106).148 The reaction of 2-bromoiodobenzene with anilinein the presence of Pd2(dba)3, dppf, and NaOt-Bu in tolueneat 100 °C afforded (2-bromophenyl)aniline in 46% yield.This compound was then treated with Pd(OAc)2 andNa2CO3 in refluxing benzene to afford the desired carbazolein 41% yield.

Bedford subsequently reported a similar one-pot carbazolesynthesis.149 Various N-substituted 2-chloroanilines werereacted with aryl bromides using Pd(OAc)2, NaOt-Bu, andPt-Bu3 in refluxing toluene (Scheme 107). Experimental

evidence suggests that the palladium-catalyzed aminationoccurs first, followed by direct arylation of the aryl chloride.Unsubstituted 2-chloroanilines afford only the aminationproduct, and none of the desired carbazole scaffold.

Larock has also reported a convenient one-pot two-stepsynthesis of carbazoles.150 The first step of the processinvolves addition ofo-iodoaniline to a benzyne intermediategenerated in situ from silylaryl triflates using CsF. Theresulting N-arylated o-iodoaniline then undergoes a pal-ladium-catalyzed intramolecular direct arylation to afford thedesired carbazole. Using this methodology, a variety ofNH-andN-substituted carbazoles could be prepared in good yields(Scheme 108). In addition, nitrogen-containing six-memberedrings and dibenzofurans could be prepared from the corre-sponding benzylamines and phenol derivatives, respectively.

An interesting coupling between an intermediate pallada-cycle derived from a bromopyridine and biphenylene hasrecently been reported by Gallagher and co-workers (Scheme109).151 Mechanistic studies suggest that the reaction pro-ceeds via initial oxidative addition followed by C-Hinsertion to form a palladacycle intermediate. Reaction withbiphenylene then affords the desired product. Additionalmechanistic studies found that the presence of ano-aryl groupadjacent to the bromide functionality was required for the

Scheme 103

Scheme 104

Scheme 105

Scheme 106

Scheme 107


reaction to proceed, further suggesting the role of anintermediate palladacycle species.

Zhu recently reported a palladium-catalyzed dominoprocess involving intramolecularN-arylation/direct aryla-tion.152,153 Various fused macrocyclic dihydroazaphenan-threnes and other medium-ring heterocycles were preparedby subjecting the corresponding bisaryl diiodide to PdCl2-(dppf) (5 mol %) and KOAc in DMSO (0.001 or 0.02 M) at120 °C (Scheme 110).

This method was later extended to the synthesis of 1,4-benzodiazepine-2,5-dione derivatives (Scheme 111). Thereaction was also found to work efficiently with “ligandless”palladium acetate as the catalyst, furnishing the desiredpolyheterocycle from the corresponding bisaryl diiodide.

Grigg described a procedure for the synthesis of phenan-threne-type heterocycles via a Rh(I)-catalyzed [2+2+2]-cycloaddition followed by a palladium-catalyzed directarylation of the newly formed aromatic functionality (Scheme112).154 Analogous substrates containing an oxygen atom inthe tether also underwent cyclization to afford a 1:1 regio-isomeric mixture of biaryl products in 82% yield (Scheme113).

A similar cyclization using iodoindoles bearing a tetheredarene has also been reported (Scheme 114).154 This approachafforded a single dihydroazaphenanthrene derivative in 62%yield, despite the possibility of regioselectivity issues.

Bringmann has extensively reported on the use of directarylation as part of an efficient strategy toward the asym-

Scheme 108

Scheme 109

Scheme 110

Scheme 111

Scheme 112

Scheme 113

Scheme 114


metric synthesis of biaryl compounds. The principle of thismethod, referred to as the “lactone method,” is illustrated inScheme 115.24,155-161 In this procedure, bromoesters areprepared by esterification ofo-bromobenzoic acids withphenols, followed by a palladium-catalyzed direct arylationto afford configurationally unstable biaryl lactones. Atro-poenantio- or atropodiastereoselective cleavage of the lactonemoiety results in an axially chiral and configurationally stableacyclic biaryl product.

The direct arylation step was initially examined for a seriesof model compounds with varying steric bulk at the axis(Scheme 116).162,163 While biaryl bond formation using

Pd(OAc)2/PPh3 occurred in good yields, improved yieldsusing Herrmann’s catalyst164-166 could be achieved for moresterically-hindered substituents.

Attempts to extend this strategy toward the synthesis ofthe bislactone ternaphthyl resulted in only the mono directarylation bromoacid (Scheme 117).167

An alternative route toward the bislactone ternaphthyl wasthen carried out via an intramolecular direct arylation,followed by deprotection of the benzyl ether and esterifica-tion of the resulting phenol and carboxylic acid (Scheme118). Conversion of the benzyl ether to the aryl triflatefollowed by intramolecular direct arylation then afforded thedesired bislactone.

Four different methods have been developed for thestereoselective lactone cleavage step (Figure 1): (1) nucleo-philic ring-opening using chiral anionic nucleophiles suchas amines, alcohols, and hydride transfer reagents, (2)activation of the lactone using a chiral Lewis acid followed

by ring-opening with a charged or uncharged achiral nucleo-phile, (3) activation of the lactone using an achiral Lewisacid followed by ring-opening with a charged or unchargedchiral nucleophile, and (4) selective chiral transition-metalη6-coordination to one of the aromatic rings followed bycleavage with an achiral nucleophile.

Scheme 115

Scheme 116

Scheme 117

Scheme 118

Figure 1.


The authors have subsequently applied this methodologytoward the synthesis of numerous axially chiral ligands,reagents, catalysts, and more than 30 natural products. Selectexamples are described in section 2.2.2.1, and more extensivereviews have also been reported.24,155-161

Recently, Larock developed a palladium migration/aryla-tion method for the synthesis of fused polycycles.48,168 Theprocess involved a palladium-catalyzed C-H activation/1,4-palladium migration to generate a key arylpalladium inter-mediate that subsequently undergoes C-C bond formationby intramolecular direct arylation (Scheme 119).

Optimal reaction conditions utilized Pd(OAc)2 (5 mol %),dppm (5 mol %), and CsOPiv in DMF at 100°C. The choiceof a highly soluble cesium pivalate base proved crucial tothe success of the reaction. Excellent yields of the desiredphenyldibenzofurans were obtained when phenoxybiphenylswere employed, while benzylbiphenyls gave poor yields ofthe corresponding product (Scheme 120). The low yields of

the latter substrates might be explained by the poor reactivity(as an intramolecular trap) of the benzyl moiety comparedto the electron-rich oxygen-substituted phenyl ring of aphenoxybiphenyl system. In addition, six-membered ringformation is not as favorable as for the five-membered ringanalogue. For six-membered ring formation, a 60:40 mixtureof the desired compound to reduced product was obtainedfrom the corresponding benzyl phenyl ether. This poor resultmight be due to the difficulty in forming a seven-memberedring palladacycle prior to the reductive elimination step.

This process also works with phenylnaphthalenes andarylphenanthrenes to generate the corresponding polycyclic

aromatic hydrocarbons in good yields (Scheme 121).168

Iodophenylnaphthalene gave a higher yield of fluoranthenecompared to the bromide starting material. In addition, theelectronics of the phenanthrene were found to be importantsince electron-rich substrates typically gave higher yieldsversus electron-deficient ones. Moreover, the typical byprod-uct in all reactions was the reduced product, which accountedfor approximately 20% of the mole balance.

This methodology was further extended to an impressivedouble palladium migration/direction arylation sequence.Treatment of 2-iodo-5-phenoxybiphenyl to the reactionconditions afforded the phenyldibenzofuran product in 88%yield (Scheme 122).168 The proposed mechanism involves

oxidative insertion of palladium into the aryl iodide, followedby 1,4-migration of palladium to the phenyl moiety by C-Hactivation. Bond rotation followed by 1,4-migration thenaffords ano-phenoxy palladium species, which undergoesdirect arylation to form the desired phenyldibenzofuranproduct (Scheme 123).

Scheme 121

Scheme 122

Scheme 123

Scheme 119

Scheme 120


These conditions were also applied to a tandem palladium-catalyzed alkyl to aryl migration/direct arylation reaction.169

Mechanistically, the authors propose that this process occursvia a carbopalladation followed by a forced 1,4-migration/intramolecular direct arylation (Scheme 124).

Various oxygen, nitrogen, and carbon linkages betweenthe alkene and aryl iodide were tolerated, affording thetetracyclic products in good to excellent yields (Scheme 125).In addition, studies indicate that electron-rich aryl iodideswere superior to electron-deficient ones.169

Another interesting example of this tandem migratorycoupling is the preparation of dibenzofuran from the corre-sponding diaryl ether (Scheme 126).169 Mechanistically, the

reaction is proposed to proceed via carbopalladation followedby a 1,4-palladium migration. Direct arylation at the 2′-position of the diaryl ether then affords the observed product.

Various carbazoles could also be prepared using a relatedpalladium-catalyzed reaction of alkynes andN-(3-iodophe-nyl)anilines.170,171 Reaction of variousN-phenyl-3-iodo-anilines with internal alkynes using Larock’s standard pal-ladium-migration conditions afforded the correspondingcarbazoles in moderate to excellent yields (Scheme 127). Anumber of internal alkynes were tolerated including aryl-,alkyl-, diaryl-, and dialkyl-substituted alkynes. In addition,the reaction tolerates both electron-withdrawing and electron-donating substituents on the aromatic ring undergoing directarylation. The absence of a substituent on the aniline nitrogenis crucial since the corresponding methyl- and phenyl-substituted amines produced none of the anticipated carbazoleproducts. The process is proposed to proceed by carbopal-ladation of the alkyne, followed by nitrogen-directed vinylto aryl palladium migration and direct arylation.

This method was also applied to the synthesis of diben-zofurans (Scheme 128).171 The reaction of 3-iodophenyl

phenyl ether with 1-phenyl-1-butyne gave the correspondingisomeric dibenzofurans in a low 30% yield. A more electron-rich substrate containing a methoxy substituent on theiodoarene moiety resulted in a significant increase in yield(80%), presumably due to the arene’s increased ability tofacilitate the vinyl to aryl palladium migration.

On the basis of deuterium labeling studies, the authorspropose that the mechanism proceeds via oxidative addition

Scheme 124

Scheme 125

Scheme 126

Scheme 127

Scheme 128


of the aryl iodide to palladium(0), followed by subsequentintermolecular carbopalladation to generate a vinylic pal-ladium intermediate (Scheme 129). Palladium migration tothe arene via a possible organopalladium(IV) hydrideintermediate then occurs. The arylpalladium species thenundergoes either palladium insertion into the C-H bond ofthe neighboring arene or electrophilic aromatic substitutionto afford the six-membered ring palladacycle. Reductiveelimination furnishes the product and regenerates the activecatalyst.

While there are many examples of intramolecular directarylations of arene C-H bonds with aryl halides, fewexamples exist for direct arylation reactions with heteroarylhalides. As part of their pioneering work in this field, Amesand co-workers reported a palladium-catalyzed intramoleculardirect arylation reaction for the synthesis of benzofuro[3,2-c]cinnoline and indolo[3,2-c]cinnolines (Scheme 130).172

More recently, the palladium-catalyzed intramoleculararylation of pyrimidine was reported in which 4-anilino-5-iodopyrimidines or 4-(aryloxy)-5-iodopyrimidines could beprepared in good yields and in one step from the corre-sponding aniline or phenol and 4-chloro-5-iodopyrimidine.173

Coupling of the iodopyrimidine to the tethered aryl groupwas then carried out to generate either the pyrimido[4,5-b]-indole or benzo[4,5]furo[2,3-d]pyrimidine in moderate togood yields (Scheme 131). Several limitations to this methodwere noted by the authors; first, strong electron-withdrawinggroups (i.e., nitro) on the phenoxy ring gave no cyclizedadduct, and second, six-membered ring formation from4-(benzyloxy)-5-iodopyrimidine failed to give the cyclizedproduct.

2.2.2. ApplicationsThe value of intramolecular direct arylation reactions is

evident from their application to the synthesis of manychemically important compounds. In this section we willdescribe the utilization of this method toward the synthesisof natural products, ligands, chiral auxiliaries, and polycyclicaromatic hydrocarbons (PAHs).

2.2.2.1. Natural Products.The lactone method describedin section 2.2.1 has been efficiently employed for theatropoenantioselective synthesis of antimalarial knipholoneand related phenylanthraquinones.174,175 Initial studies con-ducted on a model bromoester using Pd(OAc)2, PPh3, andNaOAc in DMA at 120°C furnished the desired lactone ingood yield (Scheme 132).

Extension and slight modification of these preliminaryconditions toward the direct arylation of the dibromoester36 gave the desired knipholone lactone precursor37 in arespectable 68% yield (Scheme 133). Shorter reaction timesand the use of sodium pivalate as a sterically-hindered basecompared to sodium acetate led to improved yields.

The authors have also reported the stereoselective totalsynthesis of axially chiral176 sesquiterpenes mastigophoreneA and B (Figure 2),177 which are natural products that exhibitnerve-growth-stimulating activity.178 The key steps includeda palladium-catalyzed direct arylation and a subsequentdynamic kinetic resolution using Corey’s oxazaborolidine-

Scheme 129

Scheme 130

Scheme 131

Scheme 132


borane catalyst. The optimized palladium-catalyzed intramo-lecular biaryl coupling reaction of38 resulted in the desiredbiaryl lactone39 in 39% yield together with 41% recoveredstarting material (Scheme 134). This yield was unexpected

given that model studies with similar coupling partners gaveexcellent yields.

To determine the reason for the low reactivity of38, themodel bromoester40 was subjected to the palladium-catalyzed conditions to possibly detect any relevant C-Hactivation byproducts (Scheme 135). Analysis of the reactionmixture found the presence of the cyclic biaryl ether41 in10% yield, indicating that the methoxy group in38 may beresponsible for the low yield of39. The authors propose that42 is formed by initial oxidative addition of palladium(0)and subsequent cyclometalation by C-H activation at theneighboring methoxy group. Addition of a second moleculeof 40 and reductive elimination generates43, which under-goes ring closure with decarboxylation to furnish41.

To overcome this problem, the authors modified thebromoester such that theo-methoxy group was replaced by

a diphenylmethylene acetal (Scheme 136). Intramolecularpalladium-catalyzed cyclization of this substrate now af-forded the desired lactone in 87% yield.

Bringmann has also reported a stereoselective total syn-thesis of antimalarial korupensamines.179,180 The key stepsinvolved a regioselective intramolecular direct arylation(Scheme 137) to give a configurationally labile lactone-

bridged biaryl, and the atropisomer-selective cleavage of thelactone with a variety of chiral and achiral hydride sources.Conditions employing Herrmann’s catalyst resulted in a 74%yield of the requisite biaryl intermediate, while Pd(OAc)2

and PPh3 conditions afforded a much lower 26% yield. Thecoupling occurred exclusively at the 5′-position of theisoquinoline moiety regardless of the catalyst system used.

Figure 2.

Scheme 133

Scheme 134

Scheme 135

Scheme 136

Scheme 137


This lactone method was also applied to the synthesis ofseveral other naphthylisoquinoline alkaloids including ancis-trocladisine181 (Scheme 138) and dioncophylline C182 (Scheme

139). In both cases, the palladium-catalyzed direct arylationstep afforded the desired biaryl lactone in acceptable yield.

Direct arylation has also been used by Rao for thesynthesis of the AB-biaryl fragment of vancomycin (Scheme140).183,184Treatment of the bromoarene with Pd(PPh3)2Cl2

and NaOAc in DMA at 130°C resulted in the desired biaryllactone in a modest 25% yield along with debrominatedproduct.

Bringmann and Lipshutz have also used this approach forthe atroposelective synthesis of the AB-biaryl fragment of

vancomycin.185 Use of the aryl iodide along with a moresterically-hindered base allowed for greatly improved yieldsof the desired cyclized vancomycin precursor (Scheme 141).Unfortunately, subsequent ring-opening of the lactone oc-curred in good chemical yields but with low optical purity.Therefore, an alternative approach to vancomycin was usedin which the 3′,5′-dichloro 2-iodophenyl ester44 was used.In this case, the desired biaryl lactone product was obtainedin 64% yield, and subsequent lactone ring-opening occurredin modest chemical yield and excellent diastereoselectivity.

Molander has also utilized the lactone method in anattempt to synthesize (+)-isoschizandrin (Scheme 142).186

Intramolecular direct arylation of the trimethoxyiodoarenewith Pd(PPh3)2Cl2 and NaOAc in DMA at 120°C affordedthe biaryl lactone in 87% yield.

Abe and Harayama also employed the lactone method forthe enantioselective synthesis of a key intermediate of theoptically active stegane families (Scheme 143).187 Thereaction of protected alcohols gave good yields of the desired

Scheme 138

Scheme 139

Scheme 140

Scheme 141

Scheme 142

Scheme 143


cyclized products, while use of the ester-substituted areneresulted in no reaction.

More recently, the lactone method was employed in theregio- and stereocontrolled total synthesis of benanomicinB (Scheme 144).188 The direct arylation step afforded thesterically-encumbered biaryl product in 60% yield. A similarapproach was employed in the total synthesis of pradimici-none.189

Several groups have reported the use of intramoleculardirect arylation reaction for the synthesis of gilvocarcinderivatives. In 1990, Martin reported a short and convergentsynthesis of the aglycon fragment of the gilvocarins.190 Thekey intramolecular direct arylation step employed Pd(PPh3)2-Cl2 (20 mol %) as the catalyst and resulted in the biarylcompound in 79% yield (Scheme 145).

Shortly thereafter, Suzuki reported the total synthesis ofaryl C-glycoside antibiotics gilvocarcin M and gilvocarcinV (Scheme 146).191,192 The aryl-aryl bond in gilvocarcinM was easily prepared in 90% yield using Pd(PPh3)2Cl2 (26mol %) and NaOAc in DMA at 125°C.

Synthesis of the aryl-aryl bond in gilvocarcin V from thecorresponding aryl triflate under the same conditions usedfor the synthesis of gilvocarcin M proved to be problematic.A low yield of product was obtained along with several sideproducts. It was determined in a control experiment that theobserved side products were generated by attack of acetateanion at the ester carbonyl, which is highly electrophilic dueto the presence of ano-triflate group. Use of a sterically-hindered base such as sodium pivalate was used to suppressthis side reaction, affording the desired biaryl product in 65%yield (Scheme 146).

A similar approach was reported for the synthesis of thegilvocarcin-related arnottin I.193,194Optimization of the keydirect arylation was carried out using simple model substrates

via the screening of a variety of direct arylation conditions.In doing so, the authors found that the best conditions forthe synthesis of arnottin I were the use of Pd(acac)2 (10 mol%), PPh3, and NaOAc in DMF at 150°C (Scheme 147).

A route to the core structure of the WS-5995 family, somemembers of which are structurally similar to the gilvocarcinantibiotics, was reported using a palladium-catalyzed directarylation (Scheme 148).195 In the presence of Pd(PPh3)2Cl2

Scheme 144 Scheme 146

Scheme 147

Scheme 148

Scheme 145


(5 mol %) and NaOAc, the intermediate biaryl lactonecompound was furnished in 75% yield.

Various other natural products containing a biaryl com-pound with a lactone linkage were prepared using a directarylation step. For example, the direct arylation step for thesynthesis of the graphislactones A-D (Figure 3) was carriedout using Pd(OAc)2, P(n-Bu)3, and K2CO3 in DMA to affordthe desired lactone product in 85-93% yield.196

The total synthesis of cavicularin also involved thepreparation of a lactone containing biaryl.197 The reactionemployed Herrmann’s catalyst and resulted in a 5:2 mixtureof regioisomeric products in a 38% yield (Scheme 149).

While there are many examples of natural productsynthesis involving an intramolecular direct arylation stepof a compound containing an ester tether, examples involvingcompounds with ketone tethers are scarce. One exampleinvolves the synthesis of benzo[b]fluorenones (Scheme 150),a class of compounds that have been used as intermediates

en route to the natural products stealthin C and prekinamy-cin.195,198Initial intramolecular direct arylation studies con-ducted on model substrates resulted in high yields of thedesired products (85-92%). However, when applied to thesynthesis of45, low yields or no reaction was observed(Scheme 150). Under microwave irradiation, yields for45could be improved. While microwave irradiation in transi-tion-metal-catalyzed reactions is well-known, this studyrepresents one of the few examples of the use of microwaveheating for direct arylation reactions.

Direct arylation reactions have also been used as anefficient method of generating the biaryl bond in a numberof biologically active alkaloids. Harayama and co-workershave reported the synthesis of numerous benzo[c]phenan-thridine alkaloids using an intramolecular direct arylationreaction as the key step. Select examples are illustrated inFigure 4.199 Their approach involves the coupling of naph-

thylamine and a 2-halobenzoic acid to generate aN-nap-thylbenzamide. Palladium-catalyzed intramolecular directarylation then furnishes the benzo[c]phenanthridone, whichis subsequently converted to the benzo[c]phenanthridinealkaloid (Scheme 151).

Another group of interesting biologically active naturalproduct targets that have attracted a lot of interest from thesynthetic community are theAmaryllidaceaealkaloids.200

Because of their biological activity,200 many syntheticmethods have been developed in an effort to generate variousderivatives. As a route to this interesting scaffold, Harayamareported the palladium-catalyzed intramolecular direct ary-lation of N-(2-halobenzyl)indolines.201,202In most cases thereactions gave a low-yielding mixture of cyclized dihydro-

Figure 3.

Scheme 149

Scheme 150

Figure 4.


pyrrolophenanthridine and oxidized dihydropyrrolophenan-thridone as well as the reduced benzylindoline and oxidizedbenzylindole. Using this approach, various alkaloids wereprepared including anhydrolycorine, assoanine, anhydroly-corin-7-one, and oxoassoanine (Scheme 152).

Garden reported the synthesis of a class of relatedAmaryllidaceaealkaloids using spirodioxolanes, which areformed from the correspondingN-benzylisatin deriva-tives.203,204These substrates were chosen to avoid the problemof regioselective cyclization at the indole C-7 position.Intramolecular direct arylation of these substrates gave thedesired cyclized compounds in excellent yields using Jef-fery’s conditions. Subsequent manipulation of this corecompound afforded a number of related alkaloid derivativesincluding dehydroanhydrolycorine, hippadine, anhydrolyco-rine, and anhydrolycorin-7-one (Scheme 153).

Cuny utilized a palladium-catalyzed intramolecular phenolorthoarylation for the synthesis of aporphine alkaloids suchas (()-lirinidine (Scheme 154).205,206 Optimization of thiskey step in the synthesis revealed that the use of trialky-lphosphines or trialkylphosphonium salts significantly in-creased the yield of the reaction, affording the cyclizedproduct in 58% yield.

A related direct arylation approach has also been used forthe synthesis of the aporphine alkaloid scaffold (Scheme

155).207 Optimization reactions for this catalyst systemshowed that the nature of the solvent and base drasticallyaffected the yield of the reaction. Under the optimalconditions, the direct arylation step in the formal synthesisof nuciferine afforded a 90% yield of the cyclized product.

Bringmann has also developed an atroposelective synthesisof biaryls that utilizes a chiral 1,2-diol bridge to link thetwo aryl moieties prior to the direct arylation step (Scheme156).208 The intramolecular coupling of the diacetate gavethe biaryl product in 90% yield as a 1:1 mixture ofdiastereomers, while the coupling of the more conforma-tionally rigid dioxolane gave the desired product as a singlediastereomer in 11% yield. This low yield is presumably dueto the high conformational strain imposed by the fused 5,6-ring system in the product.


Scheme 154

Scheme 155

Scheme 152


A formal enantioselective synthesis of allocolchicine wasreported employing a direct arylation using an aryl chlorideto form the seven-membered ring core (Scheme 157).209 In

addition to the desired biaryl product, a dechlorinationbyproduct was also observed in the reaction. Screeningvarious ligands found that Buchwald’s 2-(dimethylamino)-2′-(dicyclohexylphosphino)biphenyl was optimal for reducingthis byproduct.

2.2.2.2. Ligands and Chiral Auxiliaries. The lactonemethod (section 2.2.1) has also been successfully utilizedfor the preparation of several chiral auxiliaries and ligands.Selected examples are illustrated in Scheme 158 and includethe synthesis of an axially chiralC1-symmetric phosphineligand, 46, for the palladium-catalyzed stereoselective hy-drosilyation of styrenes,210 a P,N-biaryl ligand,47, used forasymmetric Suzuki coupling reactions,211 aN,O-biaryl ligand,48, for the asymmetric addition of diethylzinc to aldehydes,212

and an axially chiralC3-symmetric tripodal ligand,49, usedfor the asymmetric addition of diethylzinc to aldehydes.213

2.2.2.3. Polycyclic Aromatic Hydrocarbons.The syn-thesis of fullerene fragments, also referred to as bowl-shapedPAHs, has attracted considerable attention due to theirpotential use as starting materials for the synthesis offullerenes. While flash vacuum pyrolysis (FVP) is a commonmethod of constructing fullerene fragments, it suffers frommodest yields, low functional group tolerance due to harshreaction conditions, and difficulty in scaleup. Recently, thepalladium-catalyzed intramolecular direct arylation has been

applied to the synthesis of bowl-shaped fullerene fragmentsand other PAHs. This mild method not only allows for ahigh-yielding route to this class of PAHs, but allows forconstruction of a wide range of PAHs due to its widefunctional group tolerance.15

Rice reported the first example of an intramolecular directarylation as a route to a large number of substituted andunsubstituted PAHs in 1992 (Scheme 159).214-216

Echavarren subsequently reported the formation of avariety of fused ring systems and PAHs using a palladium-catalyzed intramolecular direct arylation.35 The cyclizationof benzylated fluorene (X) H) using Pd(OAc)2, K2CO3,and n-Bu4NBr in DMF at 130 °C for 48 h afforded thecorresponding PAH in 52% yield (Scheme 160). Substrateswith X ) NO2 and X ) F afforded the correspondingproducts in 57% and 65% yields, respectively. While thecyclization of the methoxy derivative was sluggish, replacingR4NBr with LiI allowed for the isolation of the desiredproduct in a respectable 50% yield after four days at130 °C.

Similar trends with respect to the electronic nature of thearyl bromide were also observed for the cyclization of

Scheme 156

Scheme 157

Scheme 158

Scheme 159


dibenzylated fluorenes (Scheme 161). Higher temperaturesand longer reaction times in addition to the use of LiI as anadditive was required to achieve the direct arylation ofmethoxy-containing substrates. In addition, treatment of50under milder reaction conditions resulted in selective monoary-lation of thep-nitroaryl moiety (Scheme 162).

The double intramolecular palladium-catalyzed directarylation was also applied to substrates51 and52 to affordthe corresponding products in 53% and 80% yield, respec-tively (Scheme 163).35 These conditions were then appliedto the synthesis of a C48 polyarene via a triple direct arylationto afford 54 in 71% yield.217-219

The use of direct arylation for the synthesis of benzo-[ghi]fluoranthenes from aryl triflates or bromides usingPd(PPh3)2Cl2 as the catalyst has also been reported.220 Vari-ous electron-rich and electron-poor substituents were toler-ated under the reaction conditions, affording excellent yieldsof the desired products (Scheme 164). In addition, Pd(PCy3)2-Cl2 could be used for the intramolecular direct arylation ofan aryl chloride in good yield. Although aryl chlorides havebeen reported in such reactions using Pd(OAc)2 in theabsence of a phosphine ligand, these examples suffered fromlow yields and significant byproduct formation.221

This method was also extended to the synthesis of a bowl-shaped PAH via a double palladium-catalyzed direct arylationfrom the corresponding dichloride in good to excellent yields(Scheme 165).222

Scott independently reported a similar approach for thesynthesis of a bowl-shaped PAH using aryl bromides

(Scheme 166).223 In the presence of Herrmann’s catalyst, thedesired product was obtained in 57% yield along with smallquantities of monocyclized/monodebrominated and doublydebrominated products.

An almost identical approach has also been used for thesynthesis of 1,2-dihydrocyclopenta[b,c]dibenzo[g,m]corannu-lene from the corresponding bromides in low yields (Scheme167).224

Scheme 160

Scheme 161

Scheme 162

Scheme 163

Scheme 164


More recently, various bowl-shaped PAHs were preparedinvolving two subsequent palladium-catalyzed intramoleculardirect arylations employing a dibromoarene substrate (Scheme168).225 The desired buckybowl was obtained in 37% yield,

along with small amounts of monocyclized/monodebromi-nated and didebrominated products.

Finally, the synthesis of higher oxidized metabolites ofdibenz[a,j]anthracene, which are implicated in the mecha-nism of carcinogenesis, has been reported using a directarylation reaction as one of the steps (Scheme 169).226 Useof Pd(PPh3)2Cl2 (5 mol %) and NaOAc in DMA at 140°Cafforded the desired PAH in 60% yield. The authors alsoreported the use of this approach for the synthesis of theK-region trans-9,10-dihydrodiol of benzo[g]chrysene.227

3. Direct Arylation of Heteroaryl C −H BondsAs in the direct arylation of arenes, regioselective control

for the intramolecular direct arylation often relies on a tetherapproach in order to limit the degree of freedom in thesystem. Intermolecularly, the direct arylation of heterocyclesposes a challenging task with respect to the regioselectivityof the reaction. However, unlike the intermolecular directarylation of arene systems, the inherent electronic bias ofthe heterocycle itself is often sufficient to control theregioselectivity of the direct arylation reaction, obviating theneed for directing groups. Consequently, the regioselectivityof intermolecular direct arylation primarily depends on the

heterocycle type (Figure 5), in addition to the electronicnature of the catalyst employed. More recently, other factors

such as solvent, additives (i.e., Cu(I) salts), and the stericnature of the catalyst have been used to alter the regiose-lectivity of direct arylation for heterocyclic systems.

Mechanistically, the direct arylation of heterocycles isbelieved to occur primarily via three possible pathways: (1)an electrophilic aromatic substitution, (2) a Heck-typemechanism, or (3) a carbanion cross-coupling mechanism(Scheme 170). Again, the exact mechanism (and ultimatelythe observed regioselectivity) by which the direct arylationoccurs is highly dependent upon the substrate, catalyst,reaction solvent, and additives present. Accordingly, thisportion of the review will highlight all advances in this areaof direct arylation according to heterocycle type. In addition,comments regarding the proposed mechanism and reactionregioselectivity will be presented where appropriate.

3.1. Direct Arylation of Nitrogen-ContainingHeteroaryl Compounds

3.1.1. Indoles and Azaindoles3.1.1.1. Intramolecular Aryl-Indolyl Bond Formation.

Grigg and co-workers reported the first transition-metal-

Scheme 165

Scheme 166

Scheme 167

Scheme 168

Scheme 169

Figure 5.


catalyzed direct arylation of an indole with an aryl halide in1990.228 They showed that an indole containing anN-tetheredaryl iodide underwent direct arylation at the indole 2-positionusing Pd(OAc)2, PPh3, Et4NCl, and K2CO3 in refluxingCH3CN (Scheme 171). However, 2-substituted indoles bear-

ing an aryl iodide tether at the 3-position failed to give thecorresponding 4-annulated product.

A similar reaction using an activated 3-formylindolecontaining an aryl iodide tethered at the nitrogen resulted inthe cyclized product in 70% yield. The use of bromoarenesalso resulted in the desired product, albeit in lower yields(Scheme 172).229

Higher yields for this type of cyclization were achievedusing aryl bromides, Pd(PPh3)4, and KOAc in DMA (Scheme173). These conditions were extended to a variety of 3-sub-stituted five- and seven-membered annulated indoles.230

Kozikowski subsequently utilized this methodology for thedevelopment of a new class of ligands for the antineophobicmitochondrial diazepam binding inhibitor receptor.231 Fol-lowing Kozikowski’s report, Garratt used these conditions

to prepare a large library of five-, six-, and seven-memberedannulated indoles for probing the active site of the receptorfor melatonin (Scheme 174).232

Merour and co-workers reported a similar intramoleculararylation as part of their study of the synthesis of novelsteroid hormone receptors. A variety of activated 3-cyano-and 3-formylindoles containing anN-alkylated tether wereused to generate a family of five- and six-memberedannulated indoles (Scheme 175).233 These conditions were

further extended to the annulation of five- and six-memberedazaindoles. While excellent yields were obtained for the six-membered ring system, lower yields were observed for thefive-membered ring system. This result was attributed to theformation of a kinetically more favored seven-memberedversus eight-membered palladacycle that prevented subse-quent annulation at the 2-position of indole. The authors havealso used this methodology to prepare the 3-cyclized indoleproduct from the corresponding C-2-tethered aryl bromide(Scheme 176).234,235

Scheme 170

Scheme 171

Scheme 172

Scheme 173

Scheme 174

Scheme 175


Melnyk reported a high-yielding, C-2-selective, intramo-lecular cyclization of an indole and a bromopyridine (Scheme177).236,237Since the correspondingNH-containing substrate

afforded a complex mixture of products, protection as thetertiary amide was necessary to achieve good yields. Theauthors also attempted to carry out a tandem C-2 cyclization/C-3 Heck reaction by conducting the cyclization in thepresence of acrylate. Unfortunately, the use of catalyticamounts of palladium only gave the cyclized product in lowyields. Use of stoichiometric amounts of catalyst along withan excess of acrylate (15 equiv) were required to achievemodest yields (63%) of the tandem cyclization/Heck reactionproduct.

More recently, Fagnou utilized an electron-rich NHCpalladium catalyst,33, for the intramolecular coupling ofarenes and aryl chlorides. This methodology allows for theuse of relatively cheap and accessible aryl chlorides insteadof aryl iodides or bromides (Scheme 178). Optimization

studies found that the ratio of ligand to palladium was crucialin obtaining excellent yields of the desired products, with a1.5:1 IMes:Pd ratio being more effective than a 2:1 ratio. Inaddition, halide effects238 were found to play a dramaticrole in obtaining reproducible results. In fact, treatment of[Pd(IMes)Cl2]2 with an excess of silver acetate allowed forcomplete removal of chloride from the catalyst, producingresults that were similar to those obtained from the corre-sponding Pd(IMes)(OAc)2(H2O) (33) catalyst.131 Fagnou hasalso reported the same intramolecular coupling of arylchlorides and indole in excellent yield (91%) using Pd(OAc)2/PCy3.28

These same authors have subsequently reported a one-pot tandem Heck/direct arylation reaction using a bromo-indole tethered to an aryl chloride (Scheme 179).134 Giventhat oxidative addition is known to occur faster for arylbromides versus aryl chlorides, the choice of halide on boththe indole and aryl moieties was crucial to the success ofthis tandem two-step reaction. In fact, substrates in whichthe direct arylation step occurred prior to the Heck reactionwere found to be poor substrates for this reaction, and

therefore, reversal of the order of steps was required to obtaingood yields of the desired product.

Larock has recently reported the use of 3-arylindole in apalladium-catalyzed tandem 1,4-migration/direct arylationreaction. The reaction likely proceeds via initial oxidativeaddition of palladium(0) to the aryl iodide, followed by 1,4-migration of palladium to yield an indol-2-ylpalladiumspecies. This indol-2-ylpalladium species then undergoesdirect arylation with theN-benzyl group to give the fusedtetracyclic product (Scheme 180).48,168 The authors suggest

that the higher yields and shorter reaction times comparedto those of other arene systems are a consequence of therelative ease of C-H activation for the electron-rich indole.

Larock also described a related example in which 3-iodo-1-p-tosylindole was treated with norbornene and catalyticPd(OAc)2/dppm (Scheme 181).169 Following oxidative ad-

dition, the indol-3-ylpalladium intermediate undergoessynaddition to norbornene, affording an alkylpalladium species.Since â-hydride elimination in this intermediate is notfavored, the palladium is forced to undergo 1,4-palladiummigration to the 2-position of the indole. The resulting indol-2-ylpalladium species then undergoes intramolecular cy-clization onto the tosyl group to furnish the fused ring system.

One example of the utility of intramolecular directarylation reactions is in the rapid synthesis of a variety of

Scheme 176

Scheme 177

Scheme 178

Scheme 179

Scheme 180

Scheme 181


paullone derivatives from variousN-protected indoles witharyl iodides (Scheme 182).239 In this system, yields of thecyclized products were excellent regardless of the locationof the amide tether.

This approach toward the same family of paullone deriva-tives has recently been reported by Beccalli and co-workersusing Jeffery’s conditions.240 Use of this highly reactivecatalyst system allowed for the formation of seven-, eight-,and nine-membered ring systems in modest to excellentyields (Scheme 183). Again,N-methylation of the amide wasnecessary to avoid palladium complexation.

A related route has also been reported for the preparationof a family of 6-substituted indolo[3,2-c]quinolines and6-substituted pyrido[3′,2′:4,5][3,2-c]quinolines. These com-pounds were of interest due to their structural similarity toellipticine, a potent antitumor compound. The authorsreported that protection of the secondary amide was requiredto prevent deiodination of the starting material during thepalladium-catalyzed cyclization (Scheme 184).241

The same strategy has also been employed for the synthesisof a family of phenylcarbazole derivatives for use as potentialanticancer agents.242 Cyclization of the arene indolylmale-imide gave the desired carbazole derivatives in low to goodyields depending on the protecting group and the catalyst

system used (Scheme 185). A group at Eli Lilly has alsoused this approach for the synthesis of a variety of carbazolederivatives using the correspondingNH-indole substratestethered to an aryl or thienyl bromide.243

This method has also been utilized for the intramolecularcoupling of two indole fragments as the key step in thesynthesis ofN-methylarcyriacyanin A.244 Cyclization oc-curred in good yield under palladium-catalyzed conditions(Scheme 186). In this case, the authors propose that since

synelimination is not possible, cyclization likely occurs viaa carbopalladation/base-catalyzed fragmentation pathway.Alternatively, cyclization could also occur in this case via aHeck-type coupling followed by eitheranti â-hydrideelimination245 or palladium isomerization andsynâ-hydrideelimination.

A direct arylation has also been employed for the prepara-tion of a triaza analogue of a “crushed-fullerene” fragment.41

Model studies on smaller systems found that arylation ofthe carbazole proceeded in quantitative yields under thereaction conditions (Scheme 187). Interestingly, use of anonsymmetrical carbazole was found to give a nearly equalmixture of products55 and56, casting doubt on a proposedelectrophilic aromatic substitution mechanism.

Another example of a direct arylation at the arene portionof indole was achieved by blocking the 2-position of anindole containing an aryl bromide tethered at the nitrogen(Scheme 188). This method was subsequently applied to thesynthesis of the core structures of pratosine and hippadine.246

A similar C-7 cyclization between pyridine and indolemoieties was reported as a competing side reaction in a Heckcyclization during the synthesis of a maxonine precursor(Scheme 189).247

A related example using 4-anilino-5-iodopyrimidine tocyclize onto the benzo portion of indole has also beenreported.173 In this example, two regioisomeric products wereobtained in modest yields with preference for arylation atthe 4- versus 6-position of indole (Scheme 190).

Scheme 182

Scheme 183

Scheme 184

Scheme 185

Scheme 186


3.1.1.2. Intermolecular Aryl-Indolyl Bond Formation.Ohta and co-workers reported the first intermolecular directarylation of indole using chloropyrazines. Interestingly, Ohtareported that for the palladium-catalyzed coupling of chlo-ropyrazines and indoles, the nature of the nitrogen protectinggroup on indole had a profound effect on the regioselectivityof the reaction (Scheme 191).248 While use ofN-alkyl andNH-indoles gave the desired 2-pyrazinylindole in modestyields,N-tosylindole was found to favor the 3-pyrazinylin-dole product. In addition, the steric bulk of the pyrazinyl

chloride used for the coupling was found to have a significanteffect on the regioselectivity of the arylation forN-tosyl-indole, with more sterically bulky pyrazine moieties favoringthe C-3-arylated product.

More recently, Sames reported a related palladium-catalyzed intermolecular arylation of otherN-substitutedindoles.42,249 Judicious choice of the reaction conditionsallowed for suppression of a competing palladium-catalyzedhomocoupling of iodobenzene, thereby allowing for goodyields of the 2-arylindole. The reaction scope allowed for avariety of alkyl substituents at the 1-position, as well asadditional functional groups positioned at various otherlocations around the indole ring (Scheme 192). In particular,it should be noted that this method could also be extendedto the arylation of 7-azaindoles to afford the desired 2-phenyl-7-azaindole in 85% yield.

This method also allowed for the selective C-2 arylationof indole using a limited variety ofpara-substituted electron-poor iodobenzenes (Scheme 193).249 As previously observedby Ohta,248 the use of sterically hindered aryl halides affordeda mixture of regioisomeric products under these conditions.42

Mechanistic studies suggest that the reaction proceeds viainitial electrophilic metalation at the 3-position, followed by1,2-palladium migration, deprotonation, and reductive elimi-nation (Scheme 194). Hence, the authors suggest that thepoor regioselectivity associated with bulky iodobenzenederivatives may be due to the slow 1,2-palladium migration,thereby favoring deprotonation and subsequent formation ofthe 3-metalloindole intermediate. Reductive elimination of

Scheme 187

Scheme 188

Scheme 189

Scheme 190

Scheme 191


the 3-metalloindole would then provide the observed 3-arylin-dole product.

The observations regarding the effect of the size of thearene group on the regioselectivity of the arylation led tothe development of a method to selectively arylate the C-3position of free indole via the in situ generation of a MgNsalt. Interestingly, use of a TMEDA-ligated magnesium azole

in concert with a bulky electron-rich IMes ligand onpalladium could be used to give the C-3-arylated product inexcellent selectivity and yield (Scheme 195).42

The authors later found that in situ protection of thenitrogen using MeMgCl or Mg(HMDS)2 was not requiredwhen ArRh(OPiv)2[P(p-CF3Ph)3]2 was used as the catalyst.This catalyst, prepared in situ from [Rh(coe)2Cl2]2,P(p-CF3Ph)3, CsOPiv, and ArI, afforded good yields of theintermolecularly coupled product with excellent selectivities(>50:1 for iodobenzene) (Scheme 196).250 Arylation of a

broad range of halide-, protected-amine, and ester-substitutedindoles was possible.

Mechanistic studies and X-ray analysis of the activecatalyst were used to provide some intriguing mechanisticdetails of the reaction. On the basis of these studies, theauthors propose that the active Rh(III) catalyst57 formedin situ undergoes coordination of indole and concomitantexpulsion of phosphine to generate58. On the basis of kineticisotope effects, the authors propose that the coordinatedpivalate anion assists in C-H bond dissociation, affordingcomplex 59. Reductive elimination of the 2-arylindolereleases the Rh(I) species, which is rapidly trapped by theiodoarene and CsOPiv to re-form the more stable restingcomplex57 (Scheme 197).

Sames has subsequently reported a complementary, pal-ladium-catalyzed C-2 arylation ofN-SEM-protected in-doles.251 While typically less reactive, SEM-protected indolesrepresent an attractive class of substrates due to their relativeease of deprotection. In addition, use of these conditions

Scheme 192

Scheme 193

Scheme 194

Scheme 195

Scheme 196


avoided the in situ generation of water-sensitive magnesiumazole species used for nonprotected indoles, and allowed fora catalyst system that could be applied to the arylation ofother azole derivatives in good to moderate yields (seesections 3.1.2 and 3.1.4). Treatment ofN-SEM-protectedindoles with a bulky, electron-rich NHC-bound palladiumcatalyst afforded the 2-arylindoles in good to modest yields(Scheme 198). As previously observed forN-methylindole,

use of a sterically bulky aryl iodide resulted in a mixture of2- and 3-arylated products. In addition, C-2 arylation of moredemanding 3-substituted indoles could also be carried out,albeit in lower yields.

Bellina and co-workers recently reported a palladium-catalyzed copper-mediated C-2 arylation ofNH-indole withan aryl iodide under base-free and ligandless conditions(Scheme 199).27 Although a low yield was observed for thedirect arylation of indole, higher yields were obtained forother five-membered heterocycles using these conditions (seesection 3.1.4.1).

Recently, a highly modular one-pot tandem reactioninvolving a direct arylation of indoles was reported by

Lautens.252 (Bromoalkyl)indoles were reacted with aryliodides using a palladium catalyst in the presence of nor-bornene to afford a variety of fused tricyclic indole deriva-tives (Scheme 200). The reaction tolerates a wide variety of

electron-donating and electron-withdrawing substituents onboth the aryl iodide and the indole.

Mechanistically, the reaction is proposed to occur viainitial oxidative addition of palladium(0) to the aryl iodide,followed by carbopalladation with norbornene to afford analkylpalladium species (Scheme 201). This intermediate isincapable ofâ-hydride elimination and therefore oxidativelyadds to the alkyl halide tether containing the indole moiety.The proposed palladium(IV) intermediate undergoes reduc-tive elimination to form an alkyl-aryl bond. Provided thatthe otherortho position is substituted, and therefore ef-fectively blocked from performing another palladium-catalyzed functionalization, the norbornylpalladium speciesundergoes decarbopalladative expulsion of norbornene toregenerate an arylpalladium species. The resulting arylpal-ladium species can then undergo the final intramolecularcyclization onto the indole to give a variety of six- or seven-membered annulated indoles.

More recently, there has been an emphasis on the designof direct arylation reactions that can occur under milderconditions and lower reaction temperatures. A major break-through in this area was recently reported by Sanford andco-workers in which selective C-2 arylation of indoles couldbe carried out at room temperature on the basis of a proposedPd(II)/Pd(IV) catalytic cycle.253 The authors suggest that useof a more electron-deficient Pd(OAc)2 catalyst likely resultsin a faster electrophilic palladation of indole, therebyallowing for the reaction to occur quickly, even at roomtemperature (pathway A, Scheme 202).

Reaction yields for the room-temperature coupling weremoderate to good, affording the 2-arylindoles for a broadrange of electron-rich and electron-poor arenes (Scheme 203).Furthermore, sterically-hindered 1-naphthyl ando-methylgroups could be incorporated at the desired C-2 position inexcellent (>20:1) selectivity. This extremely general protocol

Scheme 197

Scheme 198

Scheme 199

Scheme 200


was extended to the coupling of variousN-substitutedindoles.

3.1.2. Pyrroles

3.1.2.1. Intramolecular Aryl-Pyrrolyl Bond Forma-tion. Grigg reported the first example of the direct arylationof pyrrole using a tethered aryl iodide under palladium-catalyzed conditions (Scheme 204).228

The utility of this type of cyclization has since been appliedto the synthesis of the core structure of lamellarin254 as wellas a library of potent cyclin-dependent kinase inhibitors(Scheme 205).255

An additional example of the power of this methodologywas demonstrated by Trauner during the total synthesis ofrhazinilam.256 Cyclization of aryl iodide onto the pyrrole wascarried out using catalytic palladium and Buchwald’s Dav-ePhos ligand to give the desired rhazinilam precursor. The

authors report that introduction of a MOM protecting groupproved necessary to avoid deiodination of the startingmaterial, presumably via protonation of a stable palladacycleintermediate,61 (Scheme 206).

This methodology has also been used successfully in thesynthesis of the core structure of latonduine (Scheme 207).In this study, intramolecular coupling of the aryl iodide ontothe protected pyrrole was achieved in 70% yield.239 At thesame time, Beccalli and co-workers independently reporteda related intramolecular cyclization of several aryl halides

Scheme 201


Scheme 204


onto a tetheredN-methylpyrrole derivative (Scheme 208).257

In this case, the pharmaceutically interesting tricyclicheterocycles were obtained in good to excellent yields.

3.1.2.2. Intermolecular Aryl-Pyrrolyl Bond Formation.Filippini reported an interesting palladium-catalyzed directarylation ofN-metalated pyrrole with bromobenzene in whichthe nature of the cation had varying effects on productdistribution.258 While use of sodium pyrrol-1-yl gave the arylbromide-homocoupled product in quantitative yield, trans-metalation to a more hard pyrrol-1-ylzinc bromide gave thedesired 2-substituted pyrrole in 40% yield along with someof the 3-substituted pyrrole and dimerized bromobenzeneproduct. Further improvement in reaction selectivity waspossible using ZnCl2, which afforded the desired 2-substi-tuted pyrrole product in 75% yield with very little of the3-substituted pyrrole and Ullman coupling byproduct (Scheme209).

Subsequent studies by Sadighi improved the aforemen-tioned protocol such that higher yields and selectivities couldbe achieved while using lower catalyst loadings (Scheme210).259 In addition, use of the bulky, electron-rich bis(tert-

butylphosphino)biphenyl ligand allowed for the extensionof this arylation procedure to include aryl chlorides as wellas sterically demanding 2,4-dimethyl-substituted pyrrolesubstrates.

Sames has also reported several alternative procedures forthe intermolecular C-2 arylation of pyrrole. The first approachuses ArRh(OPiv)2[P(p-CF3Ph)3]2 as the catalyst system forthe C-2 arylation ofNH-containing pyrrole (Scheme 211),250

while the second relies on the use of the readily removableSEM-protected pyrrole (Scheme 212).251 Yields for this

second protocol ranged from 49% to 59% for severalelectron-poor pyrroles.

Sanford also applied her recently disclosed room-temper-ature arylation procedure to both protected and nonprotectedpyrroles. In these examples, C-2 arylation occurred selec-tively in moderate (67-69%) yields (Scheme 213).253

Ohta has also demonstrated the use of his methodologyfor the coupling of chloropyrazines and various pyrroles(Scheme 214).260 Interestingly, while coupling of theN-

Scheme 205

Scheme 206

Scheme 207

Scheme 208

Scheme 209

Scheme 210

Scheme 211

Scheme 212


methylpyrrole occurred with no evidence of any otherpyrazinylated products, the use of free pyrroles was foundto afford a 2:1 mixture of mono- to diarylated products.

Lautens and co-workers have extended their palladium-catalyzed norbornene-mediated sequential coupling reactionto the annulation of pyrroles.261 Electron-poor aromatics,which contained one blocking grouportho to the iodidefunctionality, gave good to excellent yields of the annulatedpyrroles. In addition, use of electron-rich aromatics also gavethe desired annulated pyrroles, although in somewhat loweryields (Scheme 215). The pyrrole coupling partner also

tolerated electron-withdrawing ester functionalities at the2-position, affording the 5-annulated pyrrole in moderateyields. The use of iodouracils instead of iodoarenes in thisreaction has also been reported, albeit in modest yields(Scheme 216).

3.1.3. Pyridines and QuinolinesAmes reported the first intramolecular direct arylation

reaction involving pyridine in the early 1980s. In thisexample, treatment of 2-(2-bromophenoxy)pyridine withPd(OAc)2 and Na2CO3 afforded the tricyclic compounds ina low 10% yield (Scheme 217).128

A related coupling in which two tethered pyridine moietieswere used as a model compound for the synthesis ofisocryptolepine has also been reported (Scheme 218).262

Direct arylation using the pyridyl chloride occurred in 52%yield.

de Meijere reported the use of iodopyridines in a pal-ladium-catalyzed domino coupling using norbornene (seesection 2.1.1.1 for mechanistic details) (Scheme 219).63,64

The observed norbornene-incorporated bipyridine productswere obtained in low yields.

An expedient synthesis of isocryptolepine and benzo-â-carboline isoneocryptolepine was achieved via a palladium-catalyzed intramolecular direct arylation of quinoline.262,263

Use of this direct arylation procedure allowed for the facilesynthesis of D-ring analogues of isocryptolepine for subse-quent SAR screening (Scheme 220).

Recently, access to 2-arylpyridines via an intermolecularcoupling has been achieved using palladium on charcoal inthe presence of zinc metal in water (Scheme 221).264

Although the authors discuss the possibility that the reactioncan occur via a Heck-type or radical mechanism, they favorthe latter since the aryl chloride conversion was found todecrease by 2 orders of magnitude when 5% (w/w) 2,6-di-tert-butyl-4-methylphenol (BHT) was added. Hence, theauthors propose that adsorption of the aryl halide occurs withconcomitant single-electron transfer to generate [PhX]•-

,

Scheme 213

Scheme 214

Scheme 215

Scheme 216

Scheme 217

Scheme 218

Scheme 219

Scheme 220

Scheme 221


which then undergoes anion expulsion to generate a phenylradical on the catalyst surface. Reaction of the adsorbedphenyl radical is then proposed to undergo either couplingwith a neighboring pyridine molecule or homocoupling withan adjacent phenyl radical. While these reaction conditionscould be applied to aryl chlorides, bromides, and iodides,aryl chlorides were found to afford the best yields of thedesired cross-coupled product. The authors suggest that thereason for this phenomenon is that the rate at which arylchlorides are reduced is slower than that of aryl bromidesand iodides. Therefore, in the presence of excess pyridine,the adjacent site on the palladium catalyst would most likelycontain a pyridine molecule that would then be capable of acoupling reaction. However, for aryl bromides and iodides,generation of a phenyl radical would be much more facile,increasing the likelihood of radical dimerization.

Fagnou subsequently reported a more synthetically usefulpreparation of 2-arylpyridines through a palladium-catalyzedcoupling of pyridineN-oxides and aryl bromides.265 Bothelectron-rich and electron-poor pyridineN-oxides reactexclusively at the 2-position. In addition, the aryl bromidepartner tolerated sterically-hindering as well as electron-richand electron-poor functionalities (Scheme 222). Deprotection

of the resulting 2-arylpyridineN-oxides was carried out usingPd/C in methanol in the presence of ammonium formate togive the expected 2-arylpyridine in good to excellent yields.

3.1.4. Other Nitrogen-Containing HeteroaromaticsThe direct arylation of nitrogen-containing heterocycles

is not limited to indole-, pyrrole-, and pyridine-type com-pounds. Numerous other nitrogen-containing five- and six-membered, as well as fused heterocyclic ring systems havebeen shown to undergo direct arylation (Figure 6).

3.1.4.1. Five-Membered and Fused Ring Systems.Inthe early 1980s, Nakamura reported the coupling of an aryl

iodide to an isoxazole as a key step in the total synthesis ofa lipophilic derivative of the GABA agonist muscimol.266

While an oxidative coupling strategy was first investigatedusing benzene and catalytic Pd(OAc)2 with Cu(OAc)2/oxygenas the oxidant, the authors found that use of almoststoichiometric palladium was required to obtain syntheticallyuseful yields. Hence, an alternative strategy using iodoben-zene and base was employed, allowing for the use of catalyticamounts of palladium while still obtaining the desiredcoupled product in low to moderate yields (Scheme 223).

Miura and co-workers later conducted extensive studiestoward the intermolecular palladium-catalyzed arylation ofa variety of azoles.267 Initial studies by the authors using1,2-dimethylimidazole found that both the aryl halide andbase played an important role in the reaction, and thatarylation occurred selectively at the C-5 position (Scheme224). The reaction scope for the transformation was fairly

broad, affording good to excellent yields for a variety ofelectron-rich, electron-poor, and sterically-hindered aryliodides and bromides. This method was also extended toother related azole systems including oxazoles and benzox-azoles (Scheme 225).

Scheme 222

Figure 6.

Scheme 223

Scheme 224

Scheme 225


The authors also discovered that addition of CuI increasedyields for the arylation of several azole compounds, withthe most dramatic improvement being observed for sulfur-containing heterocycles. In fact, control reactions found thateven in the absence of Pd(OAc)2, CuI alone could carry outthe arylation reaction in good yield for 1-methylbenzimida-zole (Scheme 226).267

The authors also reported that forN-methylimidazole andthiazole, the C-H bond undergoing arylation could be some-what controlled depending on the catalyst system used(Scheme 227).267 Under palladium-catalyzed conditions,arylation of the azole occurred preferentially at the C-5position, followed by subsequent arylation at C-2. Interest-ingly, carrying out the arylation with CuI in the absence ofpalladium still exclusively gave the C-2 product, albeit inlow yields. The authors proposed that this copper-mediatedarylation may occur via a Cu(I)/base-assisted nucleophilicsubstitution of the aryl iodide.268-271

For the palladium-catalyzed arylation process, the authorspropose that the reaction likely proceeds via initial oxidativeaddition of palladium(0) to the aryl halide, followed bynucleophilic attack of the azole to afford aσ-azole/arylpal-ladium(II) adduct.267 Reductive elimination would then affordthe observed arylated product (Scheme 228).

The direct arylation of other relatedN-substituted imida-zole systems has also been investigated. For example, Samesreported the C-5-selective direct arylation of SEM-protectedimidazoles in the presence of a bulky NHC-palladiumcatalyst. Under these conditions, the desired arylated productwas obtained in modest yields (Scheme 229).251 In the case

of the N-SEM-imidazole, only 3-5% of the C-2-arylatedside product was isolated.

Bellina described the selective C-5 arylation ofN-aryl-imidazoles.272 Following extensive optimization, C-5 aryla-tion could be achieved while suppressing the competitiveC-2 arylation and C-2/C-5 bisarylation pathways observedby Miura. These conditions provided the desired 1,5-di-arylimidazole in modest to excellent selectivity and in lowto moderate yields for 1-arylimidazoles bearing an electron-rich aryl group (Scheme 230).

This group subsequently reported a complementary ap-proach for the selective C-2 arylation of 1-arylimidazoles(Scheme 231).273 Through careful optimization of the catalystloading, amount of CuI additive, and base, the authors wereable to achieve a moderate-yielding and highly selective routeto 1,2-diarylimidazoles.

While most direct arylation reactions require a base,Bellina and co-workers recently reported base-free, ligandlessconditions for direct arylation.27 Various 2-arylated oxazoles,

Scheme 226

Scheme 227

Scheme 228

Scheme 229

Scheme 230


thiazoles, imidazoles, and benzimidazoles could be obtainedin good to excellent yields using this catalyst system (Scheme232).

Although copper additives have been shown to signifi-cantly improve the direct arylation of various azoles, Miurasubsequently developed conditions in which copper saltswere not required to enhance the yield for the arylation ofthiazoles.274 In screening a variety of ligands for thebisarylation of thiazole with 4-bromoanisole, it was foundthat tri-tert-butylphosphine was optimal, affording goodyields of the desired 2,5-diarylthiazole. The reaction scopeusing this catalyst system was broad, giving the arylthiazolein good yields for a variety of electron-rich and electron-neutral aryl bromides. In addition, unsubstituted and 2-sub-stituted thiazoles as well as benzothiazoles could be used inthe reaction to give the expected arylthiazole in moderate togood yields (Scheme 233).

A similar method was used to prepare a large library of2-arylbenzothiazoles with the hope of extending the resultstoward the synthesis of radiolabeled derivatives as biomarkersfor in vivo imaging of â-amyloid plaques using positronemission tomography.275 While attempts to prepare the

desired compounds using Suzuki coupling chemistry achievedlimited success, use of direct arylation allowed for thesynthesis of the required 2-arylbenzothiazole or 2-arylben-zoxazole derivatives in modest to good yields for a varietyof aryl bromides.

Another alternative method for the formation of 2-aryl-benzothiazoles was reported by Maleczka. In this study, useof poly(methylhydrosiloxane) (PMHS) in combination withCsF was found to facilitate the arylation of benzothiazoleusing either an aryl iodide or aryl nonaflate at roomtemperature (Scheme 234).276 The authors suggest that the

reaction takes place at room temperature due to the formationof a highly reactive benzothiazolylsilane intermediate,65,which subsequently undergoes rapid transmetalation andreductive elimination to form the desired 2-arylbenzothiazoleproducts.

At the same time, Mori reported a mild, C-2-selective aryl-ation of thiazoles for the preparation of tunable light emissionand liquid crystalline compounds.277 Use of PdCl2(PPh3)2/CuI and TBAF in DMSO allowed for the highly regioselec-tive arylation of thiazole at only 60°C, well below the tem-peratures typically employed for this class of transformations(Scheme 235). With a selective route for the preparation of

2-arylthiazoles in hand, the authors then used another directarylation method to afford a variety of tailored liquid crystal-line and light-emitting unsymmetrical 2,5-diarylthiazoles.

A complementary route for the regioselective formationof 2,5-diarylimidazoles and 2,5-diarylthiazoles using polymer-supported substrates has also been reported. The selectivemonoarylation of N-methylimidazole and thiazole wasachieved using an insoluble polymer resin onto which anaryl iodide moiety was immobilized.278 Following initial

Scheme 231

Scheme 232

Scheme 233

Scheme 234

Scheme 235


arylation at either C-5 or C-2 (depending on the catalystsystem used), subsequent diarylation could not occur sincethe monoarylated azole was still attached to the resin, therebypreventing any further interaction between it and anotherequivalent of aryl iodide. The resulting arylazole could thenbe hydrolyzed or further functionalized using a complemen-tary catalyst system (Scheme 236).

More recently, Fagnou reported a selective C-5 arylationof thiazole using Pearlman’s catalyst. 5-Arylthiazoles wereprepared in moderate to good yields from various iodo-arenes.133 Interestingly, no other arylation isomers werereported, and attempts to alter the regioselectivity using CuBrfailed (Scheme 237).

Bergman and Ellman have reported a rhodium-catalyzedintermolecular arylation of benzimidazoles and benzoxazolesusing a [RhCl(coe)2]2/PCy3 catalyst.279 The resulting arylatedproducts were obtained in modest to good yields (Scheme238).

Mechanistically, the authors propose that the catalytic cycleinvolves addition of benzimidazole to rhodium to generate

an NHC-type intermediate, followed by phosphine dissocia-tion and oxidative addition of the aryl iodide to give theRh(III) complex66. Phosphine association to66 along withconcomitant iodide dissociation affords complex67, whichupon reductive elimination of phenylbenzimidazole regener-ates the bis(tricyclohexylphosphine)rhodium chloride catalyst(Scheme 239).

Hoarau recently disclosed a C-2-selective arylation of ethyl4-oxazolecarboxylate using a Pd(OAc)2/Po-Tol3 catalystsystem.280 Selective C-2 arylation could be carried out toafford the desired product in 86% yield (Scheme 240). The

authors report that while solvent effects did play a minorrole in affecting the selectivity of the reaction, a greaterreduction in the amount of 5-aryloxazolecarboxylate and 2,5-diaryloxazolecarboxylate ester byproducts could be achievedusing bulky, electron-rich ligands. In light of these results,the authors proposed that the reaction proceeds via eitheran electrophilic aromatic substitution or an alternative cross-coupling pathway. Since subsequent ab initio calculationsfound that the HOMO of the heteroaromatic resides on C-2and C-5, additional experiments using CuI as a cocatalystwere carried out in an attempt to ascertain whether thereaction proceeds via a cross-coupling pathway. On the basisof this additional study, in which the use of CuI as acocatalyst failed, the authors favored a more likely electro-philic aromatic substitution mechanism.

The intermolecular coupling of an oxazole and a pyridyltriflate has also been reported for the preparation of aderivative for the inhibition of HIV-1 reverse transcriptase(Scheme 241).281 Coupling was carried out under standardconditions to afford the desired product in 34% yield.A similar approach was also reported for the preparationof 2,8-disubstituted dipyridodiazepinone using Boc-pro-

Scheme 236

Scheme 237

Scheme 238

Scheme 239

Scheme 240


tected pyrrole and 2-chloro-8-(2-phenylethyl)dipyridodi-azepinone.282

A related coupling has also been used for the preparationof a potential vascular endothelial growth factor receptor-2inhibitor (Scheme 242).283 Coupling of the pyrazine-oxazole

was carried out in a sealed tube to afford the desired productdirectly in 57% yield.

Ohta has used his conditions for the pyrazinylation of otherazole systems.260 As expected, coupling occurred selectivelyat the C-5 position, with no evidence of any other regio-isomeric products (Scheme 243).

Recently, Zhuravlev reported the mild arylation of oxa-zolo[4,5-b]pyridines using aryl iodides.284 Extensive opti-mization of the palladium source, ligand, and solvent foundthat the reaction could be carried out in modest yields for avariety of electron-rich and electron-poor aryl iodides at 30°C by using Pd(OAc)2 and PPh3 in acetone (Scheme 244).

Deuterium labeling experiments carried out using theoxazolo[4,5-b]pyridine in acetone-d6 and Cs2CO3 found thatthis substrate had a relatively low pKa value, since completedeuteration of the starting material could be obtained withinseveral hours (Scheme 245). Given the relative ease by whichthe anion is formed, the author proposed that the reactionlikely proceeds via an anion transmetalation to ArPdI,followed by reductive elimination.

The direct arylation of a variety of other related nitrogen-containing fused aromatic ring systems has also beenreported. For example, Gevorgyan reported the selective C-3direct arylation of indolizines (Scheme 246).40 Use of

electron-rich and electron-poor aryl bromides gave the3-arylindolizine selectively in moderate to good yields. Inaddition, the direct arylation of a variety of 2-substitutedindolizines could also be achieved under these conditions toafford the desired 3-arylindolizine products in good toexcellent yields.

The authors proposed four mechanistic possibilities for thisreaction: (1) a Heck-type pathway, (2) a C-H activationpathway, (3) a cross-coupling-type pathway, or (4) anelectrophilic aromatic substitution pathway (Scheme 247).Subsequent studies in which both a reductive Heck couplingand a tandem Heck cyclization with a pendent olefin at the2-position of the indolizine failed, ruling out the possibilityof a Heck-type pathway. Additional kinetic isotope effectstudies carried out by the authors using a 3-deuterioindoliz-ine-2-carboxylic acid ethyl ester revealed akH/D ) 1, therebyruling out the possibility of a coordination-assisted C-Hactivation pathway. The authors next investigated the additionof CuI, since it has been reported by Miura267 to promotethe arylation of acidic C-H bonds in heterocycles. Unfor-tunately, Gevorgyan found that the addition of CuI resultedin longer reaction times and reduced yields, thereby disfavor-

Scheme 241

Scheme 242

Scheme 243

Scheme 244

Scheme 245

Scheme 246


ing a cross-coupling-type pathway. The last remainingpossibility was an electrophilic aromatic substitution path-way. DFT calculations found that the HOMO of theheterocycle exists on the pyrrole portion of the ring, therebyconfirming that the electrophile would prefer to attack thiselectron-rich region of the heterocycle. In addition, themeasured kinetic isotope effect ofkH/D ) 1 is as expectedfor an electrophilic aromatic substitution since reestablish-ment of aromaticity is expected to be fast relative to the initialdearomatizing attack of the palladium(II) species by theheterocyclic ring. Finally, Gevorgyan carried out additionalstudies that investigated the effect of C-2 substitution of theindolizine for the palladium-catalyzed arylation versusFriedel-Crafts acylation. While the results were not identical,the observed trend in rates for various C-2-substitutedindolizines was similar for both types of reactions, furthersupporting an electrophilic aromatic substitution pathway.

An intramolecular palladium-catalyzed direct arylation ofan indolizine with a tethered aryl bromide was attemptedfor the synthesis of the benzocyclazinone derivative68.285

Although the desired cyclization at C-4 failed, the C-2-cyclized adduct was instead isolated in 43% yield (Scheme248).

The intermolecular arylation of imidazo[1,2-a]pyridineshas also been reported using Sames’ bulky NHC-palladiumcatalyst system.251 In this case, arylation occurred selectivelyat the more electron-rich position of the aromatic system,affording the desired arylated products in modest to excellentyields (Scheme 249).

Li described an intermolecular palladium-catalyzed directarylation of imidazo[1,2-a]pyrimidines with aryl bromides(Scheme 250).286 Product yields were typically high for most

types of aryl bromides. In particular, coupling with electron-deficient aryl bromides led to good yields, while couplingwith electron-rich aryl bromides was less efficient. In eithercase, coupling occurred exclusively at theπ-rich 3-positionof the heteroaromatic system.

In light of these electronic effects, the authors suggest thatan electrophilic aromatic substitution mechanism is occurring.Hence, following oxidative addition of the aryl bromide bypalladium(0), electrophilic attack by theπ-rich imidazoleportion of the imidazopyrimidine occurs, followed by base-mediated deprotonation to give an aryl(imidazopyrimidyl)-palladium(II) intermediate which subsequently undergoesreductive elimination to afford the desired 3-arylimidazo-[1,2-a]pyrimidine (Scheme 251).

A similar palladium-catalyzed direct arylation of imida-zopyrimidines using Pearlman’s catalyst and KOAc in DMA

Scheme 247

Scheme 248

Scheme 249

Scheme 250

Scheme 251


at 140°C has also been reported. In this case, the coupledproducts were obtained in high yields.133

Recently, a Merck process group reported the directarylation of an imidazo[1,2-a]pyrimidine as the key step ina short seven-step synthesis of anR2/3-selective GABAA

agonist.287 Extensive optimization revealed that use of thearyl bromide gave far superior results compared to that ofthe chloride, and that some water (<5% (w/w) with respectto the imidazotriazine) was required to achieve good conver-sion. Further studies found that direct arylation of theimidazotriazine using only 1 mol % Pd(OAc)2 could becarried out on several kilograms of material to afford thedesired product in 86% yield (Scheme 252). Use of this

approach also allowed for the synthesis of other relatedpotential GABAA agonist candidates288,289as well as a diverselibrary of compounds during the drug discovery phase thatincluded imidazo[1,2-a]pyridines, imidazo[1,2-d][1,2,4]-triazin-8-ones, and imidazo[2,1-f][1,2,4]triazin-8-ones ascoupling partners.290,291

Although the use of pyrazoles for direct arylation reactionsis uncommon, Lautens reported the arylation of a pyrazolevia a tandemorthoalkylation/intramolecular direct arylationreaction in which fused tricyclic pyrazole derivatives couldbe produced in modest yields (Scheme 253).261 While yields

were lower than those of the analogous pyrrole systems (seesection 3.1.2.2), pyrazoles represent a challenging class ofheterocycle, since the pyrazole nitrogen functionality maytightly bind to the catalyst, thereby acting as a catalyst poison.Unfortunately, all attempts to carry out the reaction in thepresence of MgO or any other Lewis acids in an attempt tolimit the coordination ability of the pyrazole failed to improvereaction yields.

An intramolecular direct arylation was used as the keystep in the synthesis of a potent antiasthmatic compound.292

While attempts to cyclize the free amide failed, alkylationof the amideNH followed by treatment with Pd(OAc)2 underJeffery’s conditions allowed for smooth cyclization to thedesired target compound (Scheme 254).

The intramolecular annulation of imidazoles and benz-imidazoles containing an aryl iodide tethered to the nitrogenatom has also been reported.293 Cyclization occurred in goodyield for the imidazole, but in somewhat lower yields forthe benzimidazole (Scheme 255). The authors suggest that

the reason for this is that the C-5 position of the imidazoleis more reactive.

A similar intramolecular direct arylation was applied tothe synthesis of the GABA receptor ligand 2-aryloxazolo-[4,5-c]quinolin-4(5H)-one.294 Coupling of an aryl iodide andan isoxazole was efficiently carried out, furnishing the fusedtricyclic product in an unoptimized 63% yield (Scheme 256).

3.1.4.2. Six-Membered Rings.Comins has reported theuse of an intramolecular palladium-catalyzed cyclization asthe final step in the synthesis of camptothecin (Scheme257).295-297 This approach has subsequently been used for

the synthesis of the camptothecin analogue GI147211C,298

and also for the assembly of ring C in the synthesis of severalhomocamptothecin analogues.299,300

Comins’ elegant approach toward the synthesis of camp-tothecin has also been utilized by others for the synthesis ofvarious natural products, including mappicine, luotonin A

Scheme 252

Scheme 253

Scheme 254

Scheme 255

Scheme 256

Scheme 257


and B, and rutaecarpine.301-304 A similar strategy was alsoutilized for the synthesis of a camptothecin-like alkaloid, 22-hydroxyacuminatine. Cyclization in this case led to thedesired 22-hydroxyacuminatine precursor in 96% yield(Scheme 258).305

A related cyclization has also been reported by Grigg asa convenient route to a family of pharmaceutically interestingisoindoles (Scheme 259).228

The intramolecular direct arylation reaction of relatedpyridazinone systems has also been reported (Scheme 260).306

Good yields of the cyclized product could be obtained withsubstrates containing the halogen on either the arene orpyridazinone moiety. In addition, this method was compatiblewith substrates containing a nitrogen or oxygen tether.

3.2. Direct Arylation of Furans and Thiophenes

3.2.1. Intramolecular Aryl−Furyl and Aryl−ThiophenylBond Formation

The first intramolecular arylation of furan and thiophenewas reported by Grigg for the preparation of a variety ofinteresting polycyclicâ-lactams (Scheme 261).307 Subsequentstudies by the same authors later utilized the same approachfor the synthesis of a large number of interesting fused six-to eight-membered heterocycles in good yields (Scheme262).308

The intramolecular direct arylation of furans, thiophenes,and pyrroles onto an anthracene core was carried out withthe corresponding dichloroanthracene derivative using Jef-fery’s conditions, providing a variety of strained polycyclicaromatic hydrocarbons in low yields (Scheme 263).309

An intramolecular direct arylation of benzothiophenes witha tethered aryl bromide was also reported using palladium-catalyzed conditions (Scheme 264).310,311Attempts using anortho blocking group to favor direct arylation to occur at

the benzo core of the benzothiophene resulted in lower yieldseven after prolonged reaction times and high catalystloadings.

Cyclization onto the C-3 position of benzothiophene as aroute to seven-membered benzazepinone ring systems hasalso been reported (Scheme 265).239 A similar cyclizationhas also been utilized for the preparation of a variety of six-membered ring thiophene analogues (Scheme 266).257

More recently, general conditions were developed for theintramolecular direct arylation of furans using aryl chloridesand iodides (Scheme 267).28 Interestingly, aryl iodides werefound to give lower yields of the desired product versus arylchlorides. This limitation could be overcome by addition ofsilver salts to the reaction to sequester the inhibitory iodide

Scheme 258

Scheme 259

Scheme 260

Scheme 261

Scheme 262

Scheme 263


released from the catalytic cycle. Under these new conditions,yields of the cyclized products obtained from the aryl iodidewere found to be comparable to those obtained using thearyl chloride. An intramolecular cyclization of aryl iodideonto thiophene was also reported in good yield.

The application of an intramolecular direct arylation offuran with an aryl iodide was also reported as a failed routetoward (()-γ-lycorane.312 Although the cyclization occurredin 57% yield (Scheme 268), all attempts to convert the

cyclized product into the required (()-γ-lycorane precursorfailed, forcing the exploration of an alternate route.

3.2.2. Intermolecular Aryl−Furyl and Aryl−ThiophenylBond Formation

While the direct aryl-benzofuran coupling using stoichio-metric palladium has been known for over 30 years,313 thefirst catalytic studies on the direct arylation of furan,thiophene, benzothiophene, and benzofuran were reportedby Ohta and co-workers almost 20 years later.314 Use ofcatalytic Pd(PPh3)4 allowed for the direct and selective C-2coupling of these heteroaromatic compounds (Scheme 269).

Aryl bromides lacking an electron-withdrawing group werefound to give little or no arylated products for all fourheteroaromatic systems, with the exception of bromobenzeneand thiophene, which gave a moderate yield of the expectedproduct. Conversely, almost all electron-poor aryl bromidesused in the study afforded the desired product in modestyields for all four heteroaromatic compounds.

These conditions have also been reported by the sameauthors for the selective pyrazinylation of unactivatedthiophenes and furan systems.260 In all cases, couplingoccurred regioselectively at the C-2 position in good yieldsusing a variety of chloropyrazoles (Scheme 270).

Walker subsequently reported a related direct arylation ofthiophene using iodopyrimidine (Scheme 271).315 Under

Scheme 264

Scheme 265

Scheme 266

Scheme 267

Scheme 268

Scheme 269

Scheme 270


these conditions, the desired heterocyclic products wereobtained in modest yields. A similar approach was laterutilized for the palladium-catalyzed coupling of a substitutedimidazole and 5-bromopyrimidine en route toward thepreparation of a novel pyrroloquinolone PDE5 inhibitors forthe treatment of erectile dysfunction.316

The selective C-2 direct arylation of activated thiophenesystems was subsequently reported by Miura.267 Particularlynoteworthy is the discovery that as in azole systems (seesection 3.1.4.1), addition of CuI significantly increased theyield of the arylated product. However, unlike the directarylation of 1-methylbenzimidazole, which can occur withcopper salts in the absence of a palladium catalyst, Pd(OAc)2

was required for the direct arylation in this system (Scheme272).

The authors also reported the triarylation ofN-(2-thienoyl)-aniline using Pd(OAc)2, Cs2CO3, and Buchwald’s JohnPhosligand in refluxing toluene (Scheme 273).317 In these

examples, the reaction is believed to occur via two directarylations followed by decarbamoylation and subsequent

coupling at the position containing the amide moiety. Onthe basis of mechanistic studies, the authors propose thatarylation likely occurs first at the C-3 position, followed byC-5 arylation. Regardless of the order of arylation, the authorsfound that the resulting mixture of C-3- and C-3/C-5-arylatedproducts both undergo decarbamoylation and subsequent C-2/C-5 or C-2 arylation, respectively, to afford the final observedtriarylated products. Interestingly, use of a C-2 tertiary amideshowed no evidence of any decarbamoylation product,instead affording the usual C-5- and C-3/C-5-diarylatedproducts (Scheme 273). The authors propose that while thefree NH allows for arylation via a coordination-assistedmechanism, use of a tertiary amide system lead to arylationvia an electrophilic addition or carbopalladation mechanism.This decarbamoylative arylation procedure has also beenextended to the bisarylation of 2-phenyl-5-thiazolecarbox-anilide and 2-phenyl-5-oxazolecarboxanilide, affording theexpected 4,5-diaryl-2-phenylthiazole or 4,5-diaryl-2-phenyl-oxazole in modest to good yields.274

Similar conditions were also applied for the bisarylationof various 2,2′-bithiophenes and 3,4-disubstituted thiophenes(Scheme 274).318 The reaction afforded good to excellentyields for a variety of aryl bromides.

While the method described above was limited to sym-metrical thiophene derivatives, unsymmetrical arylatedthiophenes could be obtained fromtert-benzyl alcohols(Scheme 275). The first aryl substituent is introduced by

Scheme 271

Scheme 272

Scheme 273

Scheme 274

Scheme 275


arylation at the C-2 position, followed by direct arylation atthe C-5 position to furnish the unsymmetrical 2,5-diaryl-thiophene product (Scheme 275). This approach has alsobeen applied to the preparation of unsymmetrical 2,2′-bithiophenes.

A complementary method of preparing unsymmetrical 2,5-disubstituted thiophene products was achieved via a selectivearylation of bromothiophenes using fluoride base and silvernitrate.319 Portionwise addition of AgNO3 was required toensure good yields of the desired C-5-arylated bro-mothiophenes. The reaction scope was broad, affording goodyields for electron-rich, electron-poor, and sterically-demand-ing aryl iodides (Scheme 276). No side reactions of the C-Brbond were observed during the course of the studies, allowingfor the subsequent derivitization of the products via a varietyof metal-catalyzed cross-coupling reactions. These conditionshave also been extended to the arylation of non-bromine-containing thiophenes.320

Additional approaches toward the direct arylation ofactivated thiophenes have also been reported by Lemaire andco-workers using Jeffery’s conditions.321-324 Again, directarylation was found to occur exclusively at the C-5 positionfor a range of sterically-demanding as well as electron-richand electron-poor aryl iodides (Scheme 277). 2-Formyl- and

2-nitrothiophene were found to give poor yields of the5-arylated thiophene, most likely due to product instability.

In a series of papers, Lemaire subsequently described arelated palladium-catalyzed thiophene-thiophene couplingfor the polymerization of alkylthiophenes (Scheme 278).324-326

Use of typical Heck type conditions allowed for a highlyregiocontrolled polymerization of iodothiophene to affordpolythiophenes with weight average molecular weights ofapproximately 6400 g/mol with moderate polydispersities.The application of this method toward the preparation ofwell-defined thiophene tetramers has also been subsequentlyreported by the same group.327

Similar conditions have also been applied to the arylationof benzo[b]thiophene systems (Scheme 279).328-330 Good

yields of the arylated products were obtained with bothelectron-rich and electron-poor benzo[b]thiophenes. Interest-ingly, nonactivated benzo[b]thiophenes such as benzo[b]-thiophene and 3-(cyanomethyl)benzo[b]thiophene were foundto give little or no product. Aryl bromides were better thanaryl iodides since they gave higher yields and selectivitiesfor direct arylation versus Ullman-type coupling.

In addition, replacing tetrabutylammonium bromide withdicyclohexyl-18-crown-6 (DCH-18-6) was found to affordbetter yields of the arylated product in shorter reaction times,as well as higher selectivity over the Ullman-type coupling(Scheme 280). These improved conditions have since been

employed for the arylation of 3-phenoxybenzo[b]thiopheneand 3-aminobenzo[b]thiophene derivatives in good yields andin short reaction times.331

An unusual ruthenium-catalyzed pentafluorophenylationof thiophene has also been reported using pentafluoroben-zenesulfonyl chloride.332 Yields for this reaction were low,typically affording a mixture of pentafluorophenylthiopheneregioisomers (Scheme 281). Mechanistically, the authors

propose that initial electron transfer from Ru(II) affords aRu(III) intermediate and a sulfonyl chloride radical anion,which then undergoes cleavage and subsequent extrusion ofSO2 to generate a pentafluorophenyl radical/Ru(III)Cl spe-cies. Radical addition to thiophene, followed by hydrogenradical abstraction by Ru(III)Cl affords the arylated productand regenerates the catalyst (Scheme 282).

Scheme 276

Scheme 277

Scheme 278

Scheme 279

Scheme 280

Scheme 281


de Meijere has also extended his palladium-catalyzeddomino coupling to 2-bromothiophenes (see section 2.1.1.1for mechanistic details) (Scheme 283).64 The observed

norbornene-containing products were obtained in low yieldsas a 1:1 mixture of di- and trithiophene products.

Recently, Sharp investigated the issue of selectivity foractivated 3-(methoxycarbonyl)thiophenes39 by carrying outa full set of factorially designed experiments in which thesolvent, base, and catalyst were screened. These studies foundthat the most important factors influencing regiochemistrywere a combination of solvent and catalyst type. In fact, useof a nonpolar solvent such as toluene in the presence of aphosphine-ligated palladium catalyst was found to selectivelyafford the C-2-arylated product, while use of a polar aproticsolvent such as NMP in the presence of a phosphine-freepalladium catalyst drastically changed the selectivity to favorarylation at the C-5 position (Scheme 284). The authors

propose that in the presence of a nonpolar solvent and aphosphine-ligated palladium catalyst, aσ-bonded palladium-(II) species is favored, thereby promoting a Heck-typereaction. Conversely, use of a polar aprotic solvent such asNMP in concert with a phosphine-free palladium catalystlikely promotes ionization of Pd-X to give a cationic

palladium species that undergoes an electrophilic reactionat the more electron-rich C-5 position of thiophene. Base-promoted deprotonation and reductive elimination of thepalladium(II) species would furnish the C-5-arylated product(Scheme 285).

The regioselective arylation of 3-(alkoxycarbonyl)furanshas also been reported since the regioselectivity of aryla-tion in these systems is typically poor.39 As with thecorresponding thiophene system, use of a nonpolar sol-vent and phosphine-ligated palladium catalyst favoredthe C-2-arylated product, while use of a polar aprotic sol-vent such as NMP and Pd/C favored the formation of theC-5-arylated product. Although electron-rich aryl bromidesfailed to give any of the arylated furan, use of electron-poor aryl bromides typically afforded moderate to goodyields of the desired product. As observed for the thio-phene systems, arylation using the C-2-selective conditionsoccurred with more regiocontrol than arylation carried outunder the corresponding C-5-selective conditions (Scheme286).

The intermolecular palladium-catalyzed C-5 arylation of2-arylfurans has also been reported for the preparation and

Scheme 282

Scheme 283

Scheme 284

Scheme 285

Scheme 286


study of metabolites of the prodrug 2,5-bis[4-(O-methoxy-amidino)phenyl]furan (Scheme 287).333

A regioselective arylation of activated furans with aryliodides or bromides was reported using PdCl2, PCy3, KOAc,and n-Bu4NBr in DMF at 110 °C (Scheme 288).334 As

observed for the corresponding thiophene systems (Scheme271), arylation of activated furans occurred selectively atthe C-5 position to give the desired products in good yields.A comparable yield has also been reported for the aryla-tion of furfural using bromobenzene and Pearlman’s cata-lyst.133

Finally, a palladium-catalyzed bisarylation of benzofuranwas attempted using 1,8-diiodonaphthalene (Scheme 289).335

In this example, the poor reactivity of benzofuran resultedin a low yield of the desired pentacyclic product even afterprolonged reaction times.

4. ConclusionsThe use of direct arylation as a route toward the formation

of a specific aryl-aryl bond has been an ongoing challengein synthetic organic chemistry over the last 20 years. Inparticular, the exploration of new catalyst systems for directarylation has grown considerably to encompass the formationof a wide range of aryl-aryl, aryl-heteroaryl, and het-eroaryl-heteroaryl bonds. More recently, studies havefocused on developing milder, lower temperature directarylation reactions. In addition, some recent studies have alsofocused on the fine-tuning of catalyst systems to allow forthe use of more inexpensive and industrially attractive aryl

chlorides. Undoubtedly, these developments will help bothsynthetic and material chemists a great deal, making directarylation a valuable tool for diverse academic and industrialapplications.

5. Notations and Abbreviationsacac acetylacetonateAc2O acetic anhydrideAcOH acetic acidAd adamantylAr arylB baseBHT 2,6-di-tert-butyl-4-methylphenolBn benzylBoc tert-butoxycarbonylBs benzenesulfonylBu butylcod cyclooctadienecoe cycloocteneCp cyclopentadienylCp* η6-pentamethylcyclopentadienylCy cyclohexyldba dibenzylideneacetoneDCH-

18-6dicyclohexyl-18-crown-6

DCM dichloromethaneDBU 1,8-diazabicyclo[5.4.0]undec-7-eneDDQ dichlorodicyanoquinoneDFT density functional theoryDG directing groupDMA dimethylacetamideDMAP 4-(dimethylamino)pyridineDMF dimethylformamideDMSO dimethyl sulfoxidedppf 1,1′-bis(diphenylphosphino)ferrocenedppm bis(diphenylphosphino)methanedppp bis(diphenylphosphino)propaneEOM ethoxymethylEt ethylequiv equivalentsFVP flash vacuum pyrolysisGABA γ-aminobutyricGC/MS gas chromatography/mass spectrometryHet heterocycleHIV human immunodeficiency virusHMDS hexamethyldisilazideHMPT hexamethylphosphorous triamideHOMO highest occupied molecular orbitalIMes 1,3-bis(mesitylimidazolyl)carbenei-Pr isopropylL ligandM metalMe methylMeOH methanolMes mesitylMOM methoxymethylMs methanesulfonylNHC N-heterocyclic carbeneNMP N-methylpyrrolidineNMR nuclear magnetic resonanceNu nucleophileOAc acetateOPiv pivalateOTf triflateo-Tol ortho-tolylPAH polycyclic aromatic hydrocarbonPDE phosphodiesterasePh phenylPhH benzenePhMe toluene

Scheme 287

Scheme 288

Scheme 289


Piv pivylPMHS poly(methylhydrosiloxane)rt room temperatureSAR structure-activity relationshipSE3 trimolecular electrophilic substitutionSEAr electrophilic aromatic substitutionSEM [2-(trimethylsilyl)ethoxy]methylTBAF tetrabutylammonium fluorideTBS tert-butyldimethylsilylt-Bu tert-butylTFA trifluoroacetic acidTf2O triflic anhydrideTFP tri(2-furyl)phosphineTHF tetrahydrofuranTMEDA tetramethylethyldiamineTMS trimethylsilylTs tosylX halideµw microwave irradiation

6. AcknowledgmentsWe thank Merck Frosst Canada and NSERC (Canada) for

an Industrial Research Chair and the University of Torontofor financial support of this work. We also thank ProfessorAntonio M. Echavarren, Professor Masahiro Miura, Dr. EricFang, Frederic Menard, and Brian Mariampillai for helpfuldiscussions. D.A. thanks the University of Toronto forfinancial support. M.E.S. thanks the University of Torontofor financial support in the form of a postgraduate fellowship.

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